The FDA has approved melphalan flufenamide (Pepaxto; melflufen) plus dexamethasone for adults with multiple myeloma whose disease is refractory to 1 or more of each type of agent: proteasome inhibitor (PI), immunomodulary agent (IMiD), and anti-CD38 monoclonal antibody.

“Melphalan flufenamide is a novel and innovative therapeutic option which is active in patients with multiple myeloma who have a refractory disease, and the product has a manageable toxicity”, says Professor Ola Landgren, Chief of Myeloma Program and Leader of Experimental Therapeutics Program, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami Health System in Miami, Florida, in a press release. “Melphalan flufenamide will complement existing treatment regimens and contribute to address the growing unmet medical need among patients with relapsed or refractory multiple myeloma.”

The approval is based on findings from the phase 2 HORIZON trial, in which melphalan flufenamde combination elicited a 23.7% overall response rate, with a median duration of response of 4.2 months. The regimen also showed activity in patients with extramedullary disease (41%).

HORIZON included 157 patients with relapsed/refractory multiple myeloma who had 2 or more prior lines of therapy, and were exposed to an IMiD and a PI and were refractory to pomalidomide (Pomalyst) and/or daratumumab (Darzalex). Participants in the study had triple-class refractory disease and/or extramedullary disease (EMD) and/or high-risk cytogenetic features. Their ECOG performance status had to fall between 0 and 2.

Patients enrolled in HORIZON were administered 40 mg of melphalan flufenamide and 40 mg of dexamethasone on day 1, and then 40 mg of dexamethasone on days 8 and 15. Patients who were 75 years or older received 20 mg of dexamethasone instead. Treatment continued in 28-day cycles until disease progression or intolerable toxicity.

“The accelerated approval of PEPAXTO in the US is an important milestone for Oncopeptides, and a major step ahead in fulfilling our mission, to bring hope to patients with difficult-to-treat hematological diseases, through innovative science,” said Marty J Duvall, Chief Executive Officer at Oncopeptides AB, in a press release. “Moving ahead, our focus is to further advance PEPAXTO. We look forward to receiving top line data from the phase 3 OCEAN-study in relapsed refractory multiple myeloma, in the second quarter. The comparative study with pomalidomide, is designed to support a future supplementary New Drug Application to expand the label.”

FDA approves Oncopeptides' PEPAXTO (melphalan flufenamide) for patients with relapsed or refractory multiple myeloma. News release. Oncopeptides AB (publ). February 26, 2021. Accessed February 26, 2021. http://cisn.co/3q2bZgq

Articles

The FDA approved melphalan flufenamide (Pepaxto; melflufen) plus dexamethasone for adults with triple-refractory multiple myeloma.

FDA Approves Melphalan Flufenamide Combo for Triple-Refractory Myeloma

Treatment with chimeric antigen receptor (CAR) T cells has induced unprecedented overall response rates (ORR) and complete response (CR) rates in patients with relapsed/refractory B cell malignancies. However, up to 50% of patients will relapse.1

 International Congress on Hematologic Malignancies, David B. Miklos, MD, PhD, associate professor of medicine (blood and marrow transplantation) at the Stanford University Medical Center, suggested that CAR agents targeting multiple antigens might hold the key to breaking through that resistance.

Previous studies have established several factors associated with relapse following CAR T therapy, including loss of the CD19 antigen and aberration in the CD58 antigen, which helps to activate engineered T cells and assists in killing cancer cells.

In a presentation at the 2018 American Society of Hematology Annual Meeting, Jean Oak, PhD, and colleagues found that 8 of 22 (36%) of patients with refractory B cell lymphomas who did not respond to treatment with axicabtagene ciloleucel (Axi-cel) or relapsed after day 28. Five patients (62%) who failed therapy had loss or downregulation of CD19, suggesting that single target antigen loss is a common mechanism of CAR T failure.2

Majzner et al analyzed CD58 status in 51 patients who were treated with axicabtagene ciloleucel for relapsed/refractory B cell lymphomas. Twelve (24%) patients had CD58 mutation or lack of expression, and 11 of those 12 had progressive disease.3

Studies have found CD4+ expression is an indication of patient response. For example, Zinaida Good, PhD, and her colleagues conducted a study seeking to identify cell features distinguishing patients with diffuse large B cell lymphoma (DLBCL) who had durable complete response (CR) at 6 months following axicabtagene ciloleucel treatment from those who had progressive disease. They found that the presence of CD4+ cells on day 7 was highly associated with clinical outcome at 6 months.4

At Stanford, investigators have been experimenting with a bispecific bivalent, single polypeptide called a “loop CAR” over the past 4 years to overcome antigen loss. Miklos showed data from a phase 1 dose escalation study of a bispecific anti CD19/CD22 using a self-contained prodigy production system to generate CAR T cells for patients with acute lymphoblastic leukemia (ALL; n = 17), primary mediastinal B-cell lymphoma (PMBCL; n = 2), and DLBCL (n = 20).

“We had day 28 overall response rates in patients with ALL of 100% and we had complete response of 88%,” Miklos said. “The Kaplan-Meier curve shows that the lymphoma fall off after 6 months was somewhere around 50%, but in truth it’s 29%. In truth, we don't think that the lymphoma responses are competitive with the commercially available products.”

Furthermore, 36% of patients with DLBCL or PMBCL and 50% of those with ALL have relapsed. Stanford, and other groups, will reapproach multi-antigen targeting with new constructs and strategies, Miklos said. There is still an unmet need for a commercially available therapy for adults with relapsed/refractory ALL.

Other investigators, however, are have some success. Nirav N. Shah, MD, and colleagues administered bispecific anti-CD20, anti-CD19 (LV20.19) CAR T cells for relapsed/refractory B cell non-Hodgkin lymphoma or chronic lymphocytic leukemia. Eighteen of 22 patients (82%) had an overall response at day 28 with a CR rate of 64%.5 This was a phase 1 dose escalation and expansion trial that to evaluate safety, as well as the feasibility of on-site manufacturing using the CliniMACS Prodigy system.

Cai Q, Zhang M, Li Z. Potential strategies against resistance to CAR T-cell therapy in haematological malignancies. 

Oak J, Spiegel JY, Sahaf B, et al. Target antigen downregulation and other mechanisms of failure after axicabtagene ciloleucel (CAR19) therapy. 

 2018;132(Suppl 1): 4656. doi:10.1182/blood-2018-99-120206

Majzner RG, Frank MJ, Mount C, et al. CD58 aberrations limit durable responses to CD19 CAR in large B cell lymphoma patients treated with axicabtagene ciloleucel but can be overcome through novel CAR engineering. Presented at: the 62nd ASH Annual Meeting and Exposition; December 5-8, 2020. Abstr 556.

Good Z, Spiegel JY, Sahaf B, et al. Identification of two CAR T-Cell populations associated with complete response or progressive disease in adult lymphoma patients treated with Axi-Cel. 

 2019;134 (Suppl 1):779. doi:10.1182/blood-2019-130815

Shah, NN, Johnson, BD, Schneider D, et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. 

.2020;1569–1575. doi:10.1038/s41591-020-1081-3

This article was originally published on OncLive as, "

Multi-Agent Therapy May Overcome CAR T Resistance in B Cell Malignancies

Up to 50% of patients with B-cell malignancies will relapse on CAR T-cell therapy. Investigators are looking in to new ways to overcome that drug resistance.

Overcoming CAR T Resistance in B-Cell Malignancies

Autologous and allogeneic BCMA-directed CAR T-cell therapies are leading to deep and durable responses in patients with heavily pretreated multiple myeloma, with a low incidence of severe cytokine release syndrome (CRS) and neurotoxicity, explained Yi Lin, MD, PhD, who added that with a pending biologics license application (BLA), the field should start to consider which patients, who don’t fit the typical clinical trial eligibility criteria, might be a candidate for the treatment in real-world practice.

On September 22, 2020, the FDA granted a priority review designation to a BLA for idecabtagene vicleucel (ide-cel; bb2121) for the treatment of adult patients with multiple myeloma who have received at least 3 previous therapies, based on data from the pivotal phase 2 KarMMa trial (NCT03361748).

“When [these approaches are] available in practice, we’ll have to look at the FDA label,” said Lin. “Putting that in context with the trial experience and also with what we’re learning in standard-of-care practice in lymphoma and leukemia, what we will need to understand beyond the approved indication [in a certain] line of therapy is really patient characteristics, such as comorbidities and so on, because we would likely not be restricted by trial criteria anymore. Understanding what a safe condition to use CAR T-cell therapy in while still preserving the efficacy of the product [is something we’ll have to determine].”

® during the 2020 Institutional Perspectives in Cancer webinar on multiple myeloma, Lin, consultant, Division of Hematology, Department of Internal Medicine, consultant, Division of Experimental Pathology and Laboratory Medicine, Department of Laboratory Medicine and Pathology, assistant professor of medicine and oncology, Mayo Clinic, discussed promising data with CAR T-cell therapy in multiple myeloma.

: How do the CAR T-cell therapies under investigation compare? Are they all leading to deep and durable responses?

: Cilta-cel [ciltacabtagene autoleucel; JNJ-68284528] and ide-cel are already in pivotal trials. With ide-cel, the BLA has been submitted to the FDA, so we’re anticipating review in early 2021. Cilta-cel is also getting ready for BLA submission to the FDA as well. Potentially in 2021, we may have these BCMA-targeted CAR T-cell therapies available in standard-of-care practice.

In these trials of heavily pretreated patients with poor-risk cytogenetics and penta-refractory disease, a single infusion of the CAR T [cells is leading to] very high overall response rates. A high percentage of these patients are having deep responses and reaching complete remission [CR] or stringent CR. A good proportion of those patients are also experiencing MRD [minimal residual disease]–negative disease. In myeloma, those are relevant metrics in terms of having more durable responses, and we’re seeing that [that’s true with] CAR T-cell therapy as well.

The median PFS [progression-free survival] is around 8.8 months for ide-cel, and the 12-month PFS rate for cilta-cel is close to 77%. That’s very exciting for a patient who has had continuous treatment. We have heard anecdotal reports from these patients on the CAR T-cell therapy trials that when they’re in remission, when they’re recovering post CAR T-cell therapy, it’s the “best they have felt.” It’s almost like before they had myeloma. Some of these metrics are being formally measured as quality-of-life outcomes in the pivotal trial. We’ve seen some of that reported as well in poster format at the 2020 ASH Annual Meeting and Exposition. Those data are very important to consider.

bb21217 is very interesting, because it’s one of these next-generation approaches we’re looking at to improve upon CAR T-cell therapy. There are a lot of emerging data regarding the phenotype of CAR T cells in myeloma, including other hematologic malignancies, [in that] the T cell that has more of a naïve with memory potential phenotype may contribute to better persistence and more active T cells. That’s one of the ways that bb21217 is trying to approach that.

During manufacturing, they’re exposing the T cells to a PI3K inhibitor to drive the phenotype functions of B cells. We’re seeing that with the CAR T cell that’s generated from patients on the study, the profiles of the CAR T-cell product do have more presence of these cells [compared with other products]. It’s still a little too early to say how the long-term clinical response will look, but initial results, in terms of response rates, are very encouraging.

Autologous products were the first to be developed, but now we’re starting to see allogeneic products as well. With longer follow-up, could they overtake autologous products?

That’s certainly a possibility. We’ve seen the data with ALLO-715; it’s very early yet. That study only has about 3 months of follow-up, but what we’ve seen has been very encouraging. The potential advantage of allogeneic CAR T-cell therapy [is that because] you’re generating [the allogeneic product] from a healthy donor, the T-cell function or the T-cell health or fitness might be better [than that of an autologous product from a patient with myeloma].

You can also make [the product] ahead of time, so it would be more ready off-the-shelf, but that comes with challenges. You are infusing T cells from somebody else, so there could be a risk for graft-versus-host-disease [GVHD], which we have seen with allogeneic stem cell transplant. This particular product comes with a lot of additional gene editing approaches to try to address that, and so far of about 31 patients who have been dosed, we haven’t seen any alarming signals for GVHD. These CAR T cells persist and are measurable in patients, which is also very encouraging, and we’re seeing early signals for response. We’re not seeing any concerns yet for the high incidence of more severe CRS, neurotoxicity, or infections.

The FDA recently approved selinexor [Xpovio] after 1 prior line of therapy. Given that we’re seeing a number of new novel agents being evaluated in earlier settings, are you concerned that when CAR T-cell therapy is approved, it’s not going to be used in the same population that it was studied in?

It will be interesting to see how it is adopted in the market. I’ve certainly heard concerns from others in the field that we’re not quite seeing a plateau in terms of PFS as we have seen in lymphoma. We have to keep in mind that these are very heavily pretreated patients that are studied on trials. I suspect, based on how the trials are designed, that the potential position of where it would be with the final FDA-approved indication would be after 3 lines of prior therapy and exposure to a proteasome inhibitor, IMiD [immunomodulatory drug], and a monoclonal antibody. If it is truly adopted for patients who would be eligible and have access to treatment centers, it could potentially buy them at least a period of time where they don’t need any therapies.

Though, we still have patients on these studies that are 2 years out or more in continued remission. I suspect because of how BCMA CAR T-cell therapy works––it’s really targeting a surface antigen, it’s not targeting particular cell signaling pathways, and we are seeing responses across other cytogenetic risks––that it wouldn’t necessarily impact how well it could function in real-world practice, but that’s something that we’ll need to learn as it becomes available.

What have we learned about managing CRS and neurotoxicity?

It’s certainly very encouraging to see that, across the CAR T-cell therapy studies, we have not generally seen a very high signal in terms of grade 3 or more severe CRS or neurotoxicity that would require ICU level monitoring. [Such scenarios have] generally [occurred] in single-digit percentages in less than 10% of cases.

There may be some component of how these CARs are designed. There may be some elements of the nature of the myeloma disease that contributes to this, but we’re also evolving in our understanding of when interventions like tocilizumab (Actemra) and steroids could be safely used to walk that balance between not losing response but preventing more severe toxicities. Within each protocol, the threshold for using tocilizumab and steroids do vary. Generally, there is a move towards using these drugs earlier in the onset of those symptoms, so patients don’t have to suffer through the more severe late effects. There’s a variable percentage of patients who get [these interventions], but it’s a higher percentage than in the earlier studies.

What novel agents caught your eye at the 2020 ASH Annual Meeting and Exposition?

I was most excited to see Allogene’s allogeneic product. What’s reassuring is that generally we are seeing response signals, but it’s a little too early to tell whether that will translate into an advantage in clinical response compared with the current generation CAR T cells. There are lots of products to keep an eye on, but it’s hard to pick a lead yet.

With the bispecific antibodies, we’re now seeing some reports from non-BCMA approaches. With a number of BCMA-targeted CAR T-cell therapies and bispecific antibody-drug conjugates, we do need to move into the non-BCMA space fairly quickly. It’s very exciting to see pretty high early response rate signals from those approaches as well. CAR T-cell therapies targeting those same antigens are also starting [to be developed], so probably by the 2021 ASH Annual Meeting and Exposition, we’ll hear some results from those studies as well. Immunotherapy approaches are moving very quickly in myeloma, and it’s always exciting to have those options for our patients.

Is it too early to start thinking about how you might approach patient selection once CAR T-cell therapies are approved?

It’s never too early to think about patient selection. It’s quite common that patients with myeloma need to get bridging therapy or continue some type of therapy while their autologous CAR T cells are being made. How that may impact or potentially be used to optimize the response of CAR T-cell therapy is not formally studied in a trial. We’ll learn from real-world practice. In terms of patient access to this product, is there a potentially broader range of conditions and comorbidities where CAR T-cell therapy can still be safely given with a reasonable expectation of response?

Are other targets emerging aside from BCMA?

GPRC5D and FcRH are the ones that are currently [being developed for] bispecific approaches. CAR T-cell therapy trials will be starting or have recently started [with those targets] as well. Thus far, based on the expression of these targets, they seem to have very limited off-target toxicities. Fingers crossed. We’ll continue to truly see that profile in the clinical trial settings. Those are the [targets] to really watch out for.

The very first report of CAR T activity in myeloma was with a CD19-directed approach. There’s still some continued effort to see if a combination of CD19 and BCMA have a role in myeloma. To that end, there are some combinations of BCMA-directed CAR T-cell therapy approaches with and CD38 or CS1. Ultimately, the novel targets are the ones to watch out for and likely will have a role, if we do see a desirable response, very quickly after BCMA-directed approaches.

US Food and Drug Administration (FDA) accepts for priority review Bristol Myers Squibb and bluebird bio application for anti-BCMA CAR T cell therapy idecabtagene vicleucel (ide-cel; bb2121). News release. Bristol Myers Squibb and bluebird bio, Inc. September 22, 2020. Accessed February 8, 2021. 

CAR T-Cell Therapy Carves Out a Role in Multiple Myeloma

CAR T-Cell Therapy Is Promising in Myeloma

Ruxolitinib (Jakafi), when administered using a pediatric dosing algorithm, was found to elicit responses in patients with chronic graft-versus-host disease (GVHD) with acceptable safety, according to preliminary findings from a retro review presented during the 2021 Transplantation & Cellular Therapy Meeting.1

The FDA approved ruxolitinib for the treatment of steroid-refractory acute GVHD in adult and pediatric patients 12 years and older in 2019 based on its ability to achieve a high rate of objective responses, as seen in Study INCB 18424-271 (NCT02953678). Despite this progress, there are limited data and understanding on how to administer ruxolitinib in patients with chronic disease and specifically how to dose the drug.2

A retrospective review of 20 patients with chronic GVHD, 4 of whom presented with overlap syndrome was conducted with the goal of providing more understanding on dosing ruxolitinib in pediatric patients with chronic GVHD. Investigators led by YunZu Michele Wang, MD, member, Division of Bone Marrow Transplantation and Immune Deficiency and instructor, Department of Pediatrics at the University of Cincinnati in Ohio, followed a weight-based dosing algorithm by which patients < 25 kg received 2.5 mg of ruxolitinib twice daily and those whose weight was ≥ 25 kg received at 5 mg dose of ruxolitinib twice daily. Patients in the study who were also being treated with tri-azole antifungal therapy had a 50% dose reduction of ruxolitinib upfront. The study protocol allowed for progressive dose increases of up to 10 mg twice daily. Response to ruxolitinib was assessed at the time of therapy initiation as well as a minimum of 30 days after treatment was initiated. Responses were evaluated per the National Institutes of Health 2014 Criteria.

The study population was compiled of patients aged 5 to 26 years. At baseline, information obtained for each patient showed that the underlying disease in the population was beta-thalassemia, DNA ligase intravenous deficiency, chronic neutrophilic leukemia, myelodysplastic syndrome, B-cell acute lymphoblastic leukemia (ALL), Epstein-Barr Virus, and hemophagocytic lymphohistiocytosis, acute myeloid leukemia, chronic disease, hemoglobin sickle cell disease, T-cell ALL, hyper-IgM syndrome, Fanconi anemia, and chronic myeloid leukemia.

Sixteen of the patients were steroid-refractory, but there were also 4 steroid-dependent patients included in the study. As prior systemic therapy, patients received a wide range of agents, some of which were rituximab (Rituxan), imatinib (Gleevec), infliximab (Remicade), and ibrutinib (Imbruvica). Most patients had also received a steroid.

Further assessment of disease characteristics in these patients showed that for the majority, chronic GVHD had affected major organs. The skin was the site of the most impact, which was observed in 11 patients. In addition, the eyes or sclerotic skin were impacted in 7 patients each, the gastrointestinal tract was affected in 6 patients, and the lungs, liver, and genitourinary system were impacted in 3 patients each. There were 2 patients whose joints were affected by their chronic GVHD and 1 whose muscles were compromised.

At the time of ruxolitinib initiation, 16 patients were also on treatment with prednisone at a median dose of 0.5 mg/kg daily (range, 0.08 mg-1.5 mg). The median time from diagnosis to ruxolitinib dosing was 181 days (range, 17-1792 days). Ruxolitinib was administered at a median dose level of 5 mg daily (range, 2.5 mg-10 mg). Notably, 6 patients in the study received the maximum daily ruxolitinib allotment of 20 mg.

Wang et al observed a response to ruxolitinib in the skin, joints, gastrointestinal tract, liver, and muscles. A 100% response rate was observed in the group of patients with sclerotic skin chronic GVHD. In addition, 2 out of 3 patients who had lung involvement experienced pulmonary function test stabilization following treatment with ruxolitinib.

Of the responses elicited by ruxolitinib therapy, 2 were complete responses in the skin, and 12 were partial responses that occurred a median of 48 days from the time ruxolitinib was first dosed. The overall response rate observed with ruxolitinib in this study was 70%. Durable responses were achieved by 13 of the 14 responders at a median of 411 days. There was also 1 patient who achieved stable disease. In the group of 16 patients who were on steroids at the time of ruxolitinib initiation, 13 patients were in the process of being weaned or were off steroids at data cutoff. Overall, 18 patients from the 20-patient cohort were still alive at data cutoff. Wang et al observed progressive disease in 4 of the study subjects, and 2 patients died from chronic GVHD that had severely progressed.

Ruxolitinib demonstrated some ability to activate the JAK/STAT pathway in this study, according to flow cytometry histograms taken before treatment and after initiation of treatment. The 

data showed fewer cases of progressive disease after ruxolitinib.

Ten patients in the study experienced adverse events (AEs) of any grade. In some cases of grade 3 or higher AEs, Wang et al intervened by holding off on treatment. In the case of grade 3 neutropenia, however, the dose of ruxolitinib was reduced. Another intervention involved holding the concurrent myelosuppressive agent in a patient who had 

, grade 3 thrombocytopenia, and grade 4 neutropenia. The final intervention of note involved starting a patient with an 

 colitis, grade 4 thrombocytopenia, and grade 2 neutropenia on a thrombopoietin receptor agonist.

Notably, none of the study subjects developed a fungal infection or pneumocystis pneumonia while receiving ruxolitinib. There was also no infection caused by neutropenia or bleeding caused by thrombocytopenia.

Findings from this retrospective analysis imply that ruxolitinib is safe and tolerable in children with chronic GVHD. Wang et al note that high infection rates are an ongoing problem for the chronic GVHD population and based on this analysis, it is still unclear whether or not ruxolitinib increases the rate of infection for patients with chronic GVHD.

Wang YM, Teusink-Cross A, Elborai Y, et al. Ruxolitinib for the treatment of chronic gvhd in children and young adults. Presented at: Presented at: 2021 Transplantation & Cellular Therapy Meetings; February 8-12, 2021; virtual. Abstract 298.

FDA approves ruxolitinib for acute graft-versus-host disease. New release. FDA. May 24, 2019. Accessed February 9, 2021. 


This article was originally published on OncLive as, "Ruxolitinib Showcases Early Efficacy, Safety in Pediatric Chronic GVHD."

Ruxolitinib Is Promising in Pediatric Chronic GVHD

The FDA approved umbralisib (Ukoniq) for the treatment of adults with relapsed/refractory marginal zone lymphoma (MZL) who had at least 1 prior anti-CD20—based regimen; and adults with relapsed/refractory follicular lymphoma (FL) who had at least 3 prior lines of systemic therapy.

“Today’s approval of UKONIQ marks a historic day for our Company with this being our first approval and we are extremely pleased to be able to bring our novel inhibitor of PI3K-delta and CK1-epsilon to patients with relapsed/refractory MZL and FL,” said Michael S. Weiss, executive chairman and CEO of TG Therapeutics, the manufacturer of the PI3K-delta and casein kinase CK1-epsilon inhibitor.

The accelerated approval was based on the open-label, multi-center, multi-cohort UTX-TGR-205 trial, which involved 69 previously treated patients with MZL and 117 patients with follicular lymphoma who had at least 2 prior systemic therapies.

Overall response rate (ORR) was 49% in patients with MZL; 16% had a complete response. Average duration of response (DOR) was not reached for this patient group.

In patients with FL, there as a 43% ORR and 3% complete response rate. Median DOR was 11.1 months.

“Despite treatment advances, MZL and FL remain incurable diseases with limited treatment options for patients who relapse after prior therapy and no defined standard of care. With the approval of umbralisib we now have a targeted, oral, once-daily option, offering a needed treatment alternative for patients,” stated Nathan Fowler, MD, Professor of Medicine at The University of Texas MD Anderson Cancer Center and the Study Chair of the UNITY-NHL MZL &FL cohorts.

The FDA recommends that umbralisib be given at 800 mg taken orally once a day with food until the patient experiences disease progression or unacceptable toxicity.

Common adverse events (AEs), which occurred in 15% or more of patients, were: creatinine, diarrhea-colitis, fatigue, nausea, neutropenia, transaminase elevation, musculoskeletal pain, anemia, thrombocytopenia, upper respiratory tract infection, vomiting, abdominal pain, decreased appetite, and rash.

Eighteen percent of patients had severe AEs, with diarrhea-colitis and infection being the most common. The most common reasons for dose modifications were diarrhea-colitis and transaminase elevation.

The prescribing information provides warnings and precautions for adverse reactions including infections, neutropenia, diarrhea and non-infectious colitis, hepatotoxicity, and severe cutaneous reactions.

“We want to thank the patients, physicians, nurses and clinical coordinators for their support and participation in our clinical trials, and the FDA for their collaboration throughout this process. We remain dedicated to patients with B-cell diseases and our mission of developing treatment options for those in need,” Weiss said.


The FDA approved umbralisib (Ukoniq) for the treatment of adults with relapsed/refractory marginal zone lymphoma (MZL) who had at least 1 prior anti-CD20&mdash;based regimen; and adults with relapsed/refractory follicular lymphoma (FL) who had at least 3 prior lines of systemic therapy.
 

FDA Approves Umbralisib for Relapsed/Refractory MZL and FL

The FDA has approved lisocabtagene maraleucel (Breyanzi) for the treatment of adult patients with certain types of large B-cell lymphoma who have not responded to, or who have relapsed after, at least 2 other types of systemic treatment.

Each dose of the CAR T-cell product is developed using each patient's own T cells. The T cells are collected and genetically modified to comprise a new gene that facilitates targeting and elimination of lymphoma cells. Once the cells are modified, they are then infused back into the individual.

"Today's approval represents another milestone in the rapidly progressing field of gene therapy by providing an additional treatment option for adults with certain types of cancer affecting the blood, bone marrow, and lymph nodes," Peter Marks, MD, PhD, director of the FDA's Center for Biologics Evaluation and Research, stated in a press release. "Gene and cell therapies have evolved from promising concepts to practical cancer treatment regimens."

Data from the phase 1 TRANSCEND NHL 001 trial showed that liso-cel resulted in an objective response rate of 73% and a CR rate of 53%, with the time to first complete response (CR) or partial response occurring at a median of 1 month.

The median duration of response has not been reached at a median follow-up of 12 months. Some 60.4% and 54.7% of patients remained in response at 6 and 12 months, respectively, lead study author Jeremy Abramson, MD, said when presenting the data at the 2019 ASH Annual Meeting.

This article was originally published on OncLive.com as, "

FDA Approves Liso-Cel for Refractory Large B-Cell Lymphoma

Liso-Cel Approved for Refractory Large B-Cell Lymphoma

Combinations of JAK inhibitors and novel agents, such as epigenetic regulators, could help prolong survival in patients with myeloproliferative neoplasms (MPNs), providing patients with more than a reduction in spleen size and symptomatic relief, explained Shella Saint Fleur-Lominy, MD, PhD, who added that for patients who have already progressed on ruxolitinib (Jakafi), fedratinib (Inrebic), momelotinib, and pacritinib could be potential second-line options.

“A lot of these agents will probably be used in combination with ruxolitinib for the most optimal response. It’s very promising to see all those different agents emerge that have an effect on disease outcome and modulation of the bone marrow,” said Saint Fleur-Lominy. “For every symptomatic patient who gets diagnosed with myelofibrosis, polycythemia vera [PV], or essential thrombocythemia [ET], we need to determine if they’re a candidate for a clinical trial, because that’s how we advance the treatment landscape.”

&#8239;during a 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Saint Fleur-Lominy, an assistant professor, Department of Medicine, at NYU Langone Health’s Perlmutter Cancer Center, discussed the current landscape of MPNs and the importance of addressing disease burden and progression. 

: What are some pathways apart from JAK that are involved in disease modulation that could become potential targets in MPNs? 

 Downstream of JAK, there are STAT dependent and independent pathways that are involved in disease modulation. A number of newer agents target those signals downstream of JAK. For example, there’s the oral kinase inhibitor alisertib, which is downstream of cNeT, which is downstream of JAK. It’s one of the molecules that is upregulated in this disease. The phase 1 study was very small, but when they analyzed bone marrow samples pre- and posttreatment, they saw that there was improvement in the degree of fibrosis, and preclinical data showed the same thing.

Other agents include epigenetic regulators. We have an ALS21 inhibitor. We have BT inhibitors. One was studied in combination with ruxolitinib in [JAK-inhibitor naïve patients] and patients who didn’t have a good response to ruxolitinib. One of the themes among these different agents is that that they modulate the disease. One of the key findings, particularly for the LSD1 inhibitor was that the bone marrow fibrosis and variant allele frequency was reduced significantly. Those diseases don’t just have the JAK mutation, they have a lot of other genes that could be mutated and that have [an effect on] survival, disease progression, and response to treatment. Having drugs that target those repeated clones is very significant. There’s also a telomerase inhibitor, and there is a phase 3 trial that is being planned.

What are some common complications of patients with MPNs that are being evaluated in studies?

Patients can have thrombotic events like clots, and we see that across the different subtypes of PV, ET, and myelofibrosis. Patients who have a low level of fibrosis can have those complications. It doesn’t matter how much fibrosis you have in the bone marrow. The risk is usually lower in younger people, but as you age, you see [patients at greater] risk. 

There is also a risk of bleeding events as well, especially in ET when people have a very high platelet count. There is also a risk of leukemic transformation because MPN is a disease that has mutations in hematopoietic stem cells, and those stem cells can transform [and] acquire new high-risk mutations and other chromosomal abnormalities and transform into acute leukemia. 

In terms of symptom burden, a very large study looked at the symptomatic manifestation of MPNs [and found that] the burden is really high. Approximately 80% of patients have a really high symptomatic burden, [ranging] from fatigue to other symptoms like reduced appetite, early satiety because of big spleen, or the big spleen causing abdominal discomfort. As high as 60% of patients have abdominal discomfort, or early satiety. Up to 80% of patients reported fatigue. 

Other symptoms like itching and night sweats [were also common]. Itching you see more with PV. Weight loss, fever, and bone pain [are additional symptoms that patients may experience]. The severity varies, so some patients have mild symptoms, and some patients have more severe symptoms. The main thing is that patients with MPNs have a very high symptomatic burden. That’s one of the reasons [a lot of studies] evaluating drugs in this disease usually use spleen reduction size and symptomatic relief as end points. 

What mutations are of the most interest in patients with PV, ET, and myelofibrosis?

One of the most common mutations is JAK2. These are diseases of abnormal JAK signaling. About 95% of patients with PV have the classic JAK2 V617F mutation, and the rest usually have [a JAK exon 12 or exon 14 mutation]. The JAK V617F mutation is found in up to 60% of patients with ET or myelofibrosis. MPL and CALR mutations are found in up to 30% [of patients]. 

How do the data with ruxolitinib and fedratinib stack up against each other?

Ruxolitinib was the first JAK inhibitor that was approved for the treatment of higher-risk myelofibrosis, and then later on was approved for the treatment of patients with PV who are intolerant to hydroxyurea or have not responded to hydroxyurea and are symptomatic. 

[The end point that was evaluated in the pivotal trial] in myelofibrosis was reduction of spleen volume and symptomatic relief. The COMFORT-I and COMFORT-II trials were both randomized controlled trials. The COMFORT-I trial had a placebo [control] and the COMFORT-II trial had best available therapy [as the control]. Both of these studies also had significant crossover. Once the investigators realized that ruxolitinib [led to a significant improvement in] patient outcomes and symptom relief, and that there was a signal for overall survival [OS], [patients were] allowed crossover [to receive ruxolitinib]. In COMFORT-II, there wasn’t really a significant [improvement in] OS, but the crossover [probably] affected that. 

In terms of PV, patients were higher risk and were not responding to hydroxyurea or were intolerant to hydroxyurea. These patients were phlebotomy dependent. A significant number of patients achieved phlebotomy independence and had a reduction in spleen volume and symptoms.

Fedratinib [Inrebic] is a selective JAK2 inhibitor compared with ruxolitinib, which is a JAK1/2 inhibitor. The thought is that [fedratinib] will be better tolerated than [ruxolitinib. When the investigators did the randomized placebo-controlled trial for fedratinib, they evaluated 2 different doses of fedratinib. At the higher dose, they saw a rare but serious complication of Wernicke encephalopathy. Because of that, we’re using the lower dose of 400 [mg].

In terms of the decrease in spleen size and symptoms, there didn’t seem to be a difference between the 400 [-mg] and the 500 [-mg] dose. Therefore, it makes sense that the 400 [-mg dose] is the one that we’re using. [Although fedratinib] results in less thrombocytopenia, ruxolitinib is the go-to drug for patients who can tolerate it. You can still use fedratinib post-ruxolitinib, but I don’t know about the reverse [sequence].

Do the data with momelotinib provide any insight into whether it should be used in the JAK inhibitor—naïve or post-ruxolitinib setting? 

We saw updated data [for momelotinib from the SIMPLIFY-1 and -2 studies] at the 2020 ASH Annual Meeting and Exposition. [Momelotinib] inhibits JAK1/2 and Activin receptor 1. One of the studies was a noninferiority study that randomized JAK-inhibitor naïve patients to ruxolitinib or momelotinib. The outcome was about the same. The other study was designed to be a superiority trial that was against best available therapy in patients who were post-ruxolitinib. The primary end point was clinical response rate, and it met the end point. [We also saw an improvement in] the total symptom scores and transfusion independence. The sustained responses and the survival benefit [for momelotinib] makes it a very promising [agent], especially for patients post-ruxolitinib compared with best available therapy.

A lot of those patients are older, and they may not be candidates for transplant. Therefore, having something that can prolong survival and make them feel better, post-ruxolitinib, is really important. When you withdraw ruxolitinib, patients can have symptoms rebound, which also seems to have an effect on survival, so if you have another JAK inhibitor that can keep them going, that’s very helpful. I’m hopeful for momelotinib and pacritinib.

MPN Efforts Set Sights on Improved Survival and Symptom Burden

New MPN Treatments Improve Survival and Symptom Burden

The FDA has approved crizotinib (Xalkori) for the treatment of pediatric patients 1 year of age and older and young adults with ALK-positive relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL).

The regulatory decision was based on data from Study ADVL0912 (NCT00939770), which showed encouraging antitumor activity with crizotinib in pediatric and adult patients with relapsed/refractory ALCL.

“We are proud to deliver the first biomarker-driven therapy for children and young adults with ALCL. [Crizotinib] offers a meaningful new treatment option for young patients with relapsed or refractory ALK-positive ALCL,” Chris Boshoff, MD, PhD, chief development officer, Oncology, Pfizer Global Product Development, stated in a press release. “[Crizotinib] transformed the treatment of ALK-positive non-small cell lung cancer as the first biomarker-driven therapy for that disease, and this approval is a notable milestone in our journey to continue to follow the science to address cancers with significant unmet need.”

In the open-label, multicenter, single-arm phase 1/2 Study ADVL0912, investigators evaluated the toxicities and optimal dose of crizotinib in younger patients with solid tumors or ALCL that has relapsed after a period of improvement or has not responded to treatment.

The primary end points of this trial focused on identifying the maximum-tolerated dose of the agent, as well as determining the recommended phase 2 dose. Investigators also set out to characterize the pharmacokinetics of crizotinib in pediatric patients with refractory disease.4 Key secondary end points were to define the antitumor activity of the drug in the phase 1 portion of the research, to evaluate the relationship between ALK positivity crizotinib response, the relationship between minimal residual disease status and response, to understand the palatability of the oral formulation of the agent, and to assess potential alterations in bone growth in the patient population.

A total of 121 patients were enrolled to the trial; this included 26 pediatric patients with relapsed/refractory, systemic ALK-positive ALCL who had previously received at least 1 systemic treatment. Patients who received crizotinib experienced an ORR of 88%. Of the 23 patients who achieved a response to treatment, 39% continued to respond for at least 6 months, while 22% continued to respond for at least 12 months.

Regarding safety, the toxicity profile of the agent in children and young adults with ALK-positive ALCL proved to be comparable to its use in those with ALK-positive and ROS1-positive non—small cell lung cancer. The most frequently reported toxicities included diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough and pruritis.

Additionally, the most common adverse effect determined to be grade 3 or higher in severity comprised neutropenia, lymphopenia and thrombocytopenia. Sixty-two percent of patients experienced grade 4 neutropenia, while 35% reported grade 4 lymphopenia, and 19% experienced grade 4 thrombocytopenia. Just under half of all study participants, or 46%, experienced visual disorders with crizotinib; 65% of those with ALCL reported this toxicity.

“Crizotinib represents an exciting new development in the treatment of this disease,” Meghan Gutierrez, chief executive officer at the Lymphoma Research Foundation, added in the release. “Researchers have made significant progress in our understanding of ALCL, which we hope will continue to improve treatment strategies and the options for children with ALCL. Today’s news builds upon this progress and provides hope to pediatric patients with ALCL and their loved ones.”

1. Pfizer's Xalkori (crizotinib) approved by FDA for ALK-positive anaplastic large cell lymphoma in children and young adults. News release. Pfizer Inc. January 14, 2021. Accessed January 14, 2021. http://bit.ly/35YmdaL.

2. FDA accepts supplemental new drug application for Pfizer’s Xalkori (crizotinib) for the treatment of pediatric ALK-positive anaplastic large cell lymphoma. News release. Pfizer Inc. January 14, 2021. Accessed September 23, 2020. https://bit.ly/2RRX75J.

3. Gambacorti-Passerini C, Orlov S, Zhang L, et al. Long-term effects of crizotinib in ALK-positive tumors (excluding NSCLC): a phase 1b open-label study. Am J Hematol. 2018;93:607-614. doi:10.1002/ajh.25043

4. Crizotinib in treating younger patients with relapsed or refractory solid tumors or anaplastic large cell lymphoma. ClinicalTrials.gov. Updated June 9, 2020. Accessed September 23, 2020. https://clinicaltrials.gov/ct2/show/NCT00939770.

5. Mossé YP, Voss SD, Lim MS, et al. Targeting ALK with crizotinib in pediatric anaplastic large cell lymphoma and inflammatory myofibroblastic tumor: a Children's Oncology Group study. J Clin Oncol. 2017;35(28):3215-3221. doi:10.1200/JCO.2017.73.4830

FDA Approves Crizotinib for Pediatric and Young Adult ALK+ Anaplastic Large Cell Lymphoma

FDA Approves Crizotinib for Pediatric/Young Adult ALK+ Anaplastic Large Cell Lymphoma

The FDA has granted fast track designations to cavrotolimod (AST-008) for use in combination with a PD-1 therapy in patients with locally advanced or metastatic Merkel cell carcinoma (MCC) that is refractory to previous PD-1 blockade and for use in combination with a PD-1/PD-L1 agent in those with advanced or metastatic cutaneous squamous cell carcinoma (CSCC) that is refractory to previous PD-1/PD-L1 blockade.

“There is an urgent need to investigate novel immunotherapeutic agents such as cavrotolimod that can be given to enhance the clinical efficacy of immunotherapy, particularly in patients with refractory solid tumors,” Adil Daud, MD, a clinical professor at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center and principal investigator in the phase 1b/2 trial of the agent, stated in a press release.

A spherical nucleic acid toll-like receptor 9 agonist, cavrotolimod was developed to activate the innate and adaptive immune systems to elicit strong antitumor responses in patients who receive it.

In the phase 1b dose-escalation portion of the trial, investigators set out to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cavrotolimod both as a single agent and in combination with pembrolizumab (Keytruda) or cemiplimab-rwlc (Libtayo); one of the key objectives was to determine the recommended phase 2 dose (RP2D) for the drug.

The trial enrolled a total of 20 patients; of these patients, 10 had melanoma, 5 had MCC, 2 had CSCC, 2 had head and neck squamous cell carcinoma, and 1 had leiomyosarcoma. At the time of enrollment, the majority of participants (85%) had experienced disease progression while receiving treatment with a PD-1 therapy.

Results from the trial showed that cavrotolimod elicited an overall response rate (ORR) of 21% (n = 4/19); the ORR was even higher, at 33%, in the group of patients who received the agent at the highest dose of 32 mg (n = 2/6); as such, this was identified as the recommended phase 2 dose of the drug.

Additionally, overall responses were observed in 2 patients with advanced MCC and 2 patients with melanoma. Notably, 3 of the 4 patients who responded to treatment had been progressing on PD-1 therapy at the time of enrollment. Forty percent of patients with MCC responded to treatment with cavrotolimod; this included 1 complete response (CR).

Beyond the 4 confirmed responses observed with the agent, 1 patient with CSCC and 2 patients with melanoma experienced a reduction in target tumor lesions; this translated to 37% of evaluable patients having reported target tumor shrinkage. Notably, systemic effects were also reported, with noninjected tumors distant from injected lesions also showing regression.

The median duration of response to cavrotolimod had not yet been reached in the 4 patients who responded; at a median follow-up of 11 months, none of the responders had experienced disease progression.

Pharmacodynamic data revealed an increase in serum cytokines/chemokines, activation of immune cells, and immune cell infiltration in the tumor, thus supporting the efficacy information yielded.

Regarding safety, the agent was found to have favorable tolerability. Although 98% of patients experienced treatment-emergent toxicities, these effects were only grade 1 or 2 in severity. No serious adverse effects associated with treatment were reported at the time of data cutoff. The most frequently reported effects included flu-like symptoms and injection site reactions.

In the phase 2 portion of the trial (NCT03684785), which is ongoing, investigators are examining the agent in combination with pembrolizumab or cemiplimab in the treatment of patients with locally advanced or metastatic MCC or CSCC, respectively.3 All participants experienced progressive disease, despite treatment with an FDA-approved PD-1 or PD-L1 inhibitor.

In the phase 1b portion of the trial, investigators utilized a 3+3 dose-escalation design and set out to assess escalating or intermediate dose levels of the agent administered with a fixed dose of pembrolizumab in patients with solid tumors. Here, 5 ascending doses of the agent were evaluated in 5 cohorts, with at least 3 participants enrolled to each group. The objective was to determine the RP2D for the drug.

In this portion of the research, participants are dosed twice with single-agent cavrotolimod and then will go on to receive pembrolizumab at the start of the second treatment cycle. Once the maximum-tolerated dose or highest escalation cohort has been reached, or significant efficacy has been observed at a given dose level and the RP2D dose is identified, then a 2-stage expansion cohort will be evaluated.

Preliminary data presented in December 2019 from the phase 1b portion of the research, cavrotolimod monotherapy or in combination with pembrolizumab was found to induce cytokine and chemokine expression and activate immune cells in patients with MCC.

Of 4 total MCC patients, 1 who had previous disease progression on a PD-1 inhibitor, achieved stable disease with a reduction in their tumor lesion for longer than 12 weeks. Another patient with MCC experienced a CR in their target lesion and a confirmed overall partial response that persisted for longer than 24 weeks. Nine participants experienced disease progression, 2 had not yet been evaluated, and 1 patient was determined to be unevaluable.

Enrollment for the phase 1b portion of the trial has been completed with a total of 20 patients having received treatment with cavrotolimod.

In the phase 2 portion of the research, investigators will examine the RP2D of the agent in 2 cohorts: those with MCC and those with CSCC. In the cohort with MCC, patients received intravenous (IV) cavrotolimod in combination with a fixed, standard dose of pembrolizumab. In the cohort with CSCC, patients received IT cavrotolimod plus a fixed, standard dose of cemiplimab.

Moreover, this portion of the research will also include an exploratory expansion cohort, in which investigators will examine cavrotolimod plus pembrolizumab in participants with other advanced solid tumors, such as melanoma, who experienced disease progression on a PD-1 inhibitor.

“I am encouraged by the phase 1b dose-escalation results and excited about the potential of cavrotolimod to address the significant unmet need facing these patients,” Michael Wong, MD, PhD, professor at the University of Texas MD Anderson Cancer Center and principal investigator of the phase 1b/2 clinical trial of the agent, added in the release.

1. Exicure granted two fast track designations for cavrotolimod (AST-008) from the US Food and Drug Administration. News release. Exicure, Inc. January 11, 2021. Accessed January 11, 2021. http://bwnews.pr/2LHDWLY.

2. Pipeline: Cavrotolimod (AST-008). Exicure, Inc. website. Accessed January 11, 2021. http://bit.ly/3oNKCqV.

Intratumoral cavrotolimod combined with pembrolizumab or cemiplimab in patients with advanced solid tumors. ClinicalTrials.gov. Updated October 23, 2020. Accessed January 11, 2021. https://www.clinicaltrials.gov/ct2/show/NCT03684785.

FDA Grants Fast Track Status to Cavrotolimod for Merkel Cell Carcinoma, CSCC

Cavrotolimod Granted Fast Track Status for Merkel Cell Carcinoma, CSCC

The reversible BET inhibitor CC-90010 was found to have preliminary antitumor activity in patients with heavily pretreated, advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma, according to the updated results of a phase 1 study (NCT03220347) presented during the 2020 ESMO Virtual Congress.

In patients enrolled on part A of the study (n = 69), the agent elicited a clinical benefit rate (CBR) of 17.4% was reported (n = 12; 95% CI, 9.3-28.4) along with an objective response rate (ORR) of 2.9% (n = 2; 0.4-10.1).

During treatment, 1 patient (1.4%) with diffuse astrocytoma achieved a complete response (CR) and continued on the treatment for 18 cycles until before experiencing disease progression. An additional patient with endometrial carcinoma achieved a partial response (PR) and was able to complete 8 cycles of treatment. Ten patients were able to maintain stable disease (SD) for at least 4 months; 3 patients had prolonged SD for 24 cycles, 1 patient had SD for 16 cycles, and 2 patients had SD for 15 cycles. Two patients with stable disease are still receiving treatment at cycles 28 and 24.

In part B of the study (n = 14), CC-90010 induced a CBR of 21.4% (n = 3; 95% CI, 4.7-50.8) along with an ORR of 14.3% (95% CI, 1.8-42.8). One patient with diffuse large B-cell lymphoma (DLBCL) experienced a CR and finished 5 cycles of treatment, while another patient with the same disease achieved a PR and completed 3 cycles. Two patients achieved SD (14.3%), 1 (7.1%) of whom maintained stability for 4 months or longer.

“CC-90010 was well-tolerated and showed preliminary antitumor activity in heavily pretreated patients with advanced solid tumors and relapsed DLBCL,” Victor Moreno Garcia, PhD, director of Clinical Research at the Phase 1 Trials Unit START at University Hospital Fundación Jiménez Díaz, said in a presentation during the meeting. “Treatment-related adverse effects [TRAEs] were mostly mild and manageable with dose interruptions and reductions.”

A potent and reversible small-molecule BET inhibitor, CC-90010 preferentially binds to bromodomain-containing proteins. The agent was found to lead to tumor reduction when evaluated in xenograft models and encouraging activity in patients with advanced malignancies.2 Because BET proteins are key players in the regulation of MYC oncogene expression, investigators hypothesized that CC-90010 may represent a potential effective option for patients with high-grade B-cell lymphoma, particularly those who have MYC rearrangements.

The multicenter, open-label, first-in-human phase 1 trial was comprised of 2 parts; part A focused was the dose-escalation phase of the trial, while the ongoing part B portion is evaluating the safety and efficacy of the agent in an expansion cohort.

To be eligible for the dose-escalation portion of the study, patients needed to be 18 years of age or older with either advanced unresectable solid tumors (n = 67) or relapsed/refractory DLBCL (n = 2). Additionally, patients needed to have an ECOG performance status of 0-1 and have progressed on or were unable to tolerate a standard anticancer treatment.

Numerous doses of CC-90010 were evaluated in part A, although the 45-mg dose, delivered 4 days on and 24 days off, was selected as the recommended phase 2 dose; the 30-mg dose, delivered 3 days on and 11 days off, was selected as an alternative dosing regimen. Dose escalation was completed on December 10, 2018 and the primary objectives of part A were reached.

Two cohorts of patients received the 45-mg dose of CC-90010: cohort 1 was comprised of 14 patients with relapsed/refractory DLBCL and cohort 2 was comprised of 1 patient with advanced basal cell carcinoma and 1 patient with NUT midline carcinomas. Cohort 1 is ongoing and cohort 2 has stopped. The recently-opened third cohort is comprised of patients with relapsed/refractory DLBCL who are receiving the agent at the 30-mg dose.

Patients enrolled on the dose-escalation portion of the trial had a median age of 57 years and were primarily male (n = 38; 55%). Meanwhile, those included in the safety and efficacy portion of the study had a median age of 63.5 years and 57% were male (n = 8). In part A, 48% (n = 33) of patients had an ECOG performance status of 0, while 52% (n = 36) had a status of 1; in part B, these percentages were 21% and 79%, respectively. The median number of previous systemic cancer therapies received was 4 in both parts of the trial.

Moreover, the majority of the patients, of 97% (n = 67) in part A had solid tumors, while 3% (n = 2) had DLBCL. Eighty-six percent (n = 12) of the patients included in part B had DLBCL, while 14% (n = 2) had solid tumors. Notably, at the time of enrollment, stage IV cancer was observed in the majority of patients who had solid tumors.

The median treatment duration was 8 weeks, and the majority of patients were able to receive their planned dose. During the dose-escalation portion of the trial, the monthly dosing schedule of 4 days on and 24 days off was found to have the lowest number of dose modifications compared with other schedules examined. Additionally, the monthly schedule of 4 days on and 24 days off and the biweekly dosing schedules of 3 days on and 11 days off were found to have safety profiles that were more favorable than that of the weekly dosing schedule.

“Adverse effects [AEs] were the most common reason for dose reduction—12% in part A and 14% in part B&mdash;and interruption&mdash;45% in part A and 43% in part B,” noted Moreno. “One patient in part A discontinued [treatment] due to an AE that was not treatment related.”

In total, 32 patients in part A had progressive disease (46.4%) and 12 were not evaluable (17.4%). Patients on dose escalation portion of the study were additionally reported to have had a median overall survival (OS) of 180 days (95% CI, 161-254) and a median progression-free survival (PFS) of 57 days (95% CI, 52-81). Four patients in part B experienced progressive disease (7.1%) while another 6 were not evaluable (42.9%). Patients enrolled on part B portion reportedly had a median OS of 102 days (95% CI, 92-NE) and a median PFS of 60 days (95% CI, 12-126). One heavily pre-treated patient who had been diagnosed with relapsed/refractory DLBCL experienced a 57% regression of target lesions following treatment.

The majority of treatment-related AEs were found to be mild or moderate in severity, reversible, and easily managed through dose adjustments and/or supportive care. The high rate of thrombocytopenia reported in part B (any grade, 79%; n = 11; grade 3/4, 64%; n = 9) is reflective of the high number of patients with hematologic malignancies on the trial, according to Moreno. Other common AEs reported in part B included anemia (any grade, 43%; grade 3/4 28%), neutropenia (any grade, 29%; grade 3/4 21%), nausea (any grade, 29%), and asthenia (any grade 21%; grade 3/4 7%). No treatment-related deaths occurred.

“This study is ongoing in [patients with] relapsed/refractory DLBCL and advanced solid tumors at the recommended phase 2 doses and relapsed/refractory DLBCL at an alternative dosing regimen," Moreno concluded.

1. Moreno V, Braña Im Sepulveda JM, et al. CC-90010, a reversible, oral bromodomain and extra-terminal (BET) inhibitor in patients with advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma: updated results of a phase 1 study. Presented at: 2020 ESMO Virtual Congress; Virtual. September 19-21, 2020. Accessed September 28, 2020. Abstract 5270.

2. Moreno V, Sepulveda JM, Vieito M, et al. Phase I study of CC-90010, a reversible, oral BET inhibitor in patients with advanced solid tumors and relapsed/refractory non-Hodgkin's lymphoma. Ann of Oncol. 2020;S0923-7534(20):36381-X. doi:10.1016/j.annonc.2020.03.294

3. Mertz JA, Conery AR, Bryant BM, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Natl Acad Sci USA. 2011;108(40):16669-16674. doi:10.1073/pnas.1108190108.

Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904-917. doi:10.1016/j.cell.2011.08.017

BET Inhibitor CC-90010 Shows Activity in Advanced Solid Tumors, Relapsed/Refractory Non-Hodgkin Lymphoma

Blood Cancers