Silas Inman

In the phase I CRB-402 study, patients with heavily pretreated relapsed/refractory multiple myeloma had high rates of very good partial responses (VGPRs) or better to the anti-BCMA CAR T cell therapy bb21217, according to updated results presented at the 2019 American Society of Hematology (ASH) Annual Meeting. Minimal residual disease (MRD) negativity was observed in most patients with a confirmed response.&nbsp;

The longest follow-up from the study (23 months) was available for patients receiving a 150 x 10

dose of bb21217, which was the lowest dose explored in the study. In this cohort, the complete remission (CR) or stringent CR (sCR) rate was 33% and the VGPR rate was 50%, for an objective response rate (ORR) of 83%. All patients in this group were MRD-negative and the median duration of response was 11.1 months.

dose cohort, the median duration of response is promising at 11.1 months. In the higher dose cohorts, follow up is short but there are no confirmed responders who have progressed," Jesus G. Berdeja, MD, from the Sarah cannon Research Institute, said during a presentation of the results. "The safety profile of bb21217 in this phase I study of relapsed/refractory multiple myeloma remains consistent with known toxicities of CAR T-cell therapies."

As part of the bb21217 manufacturing process, the CAR T-cell therapy bb2121 is cultured with the PI3 kinase inhibitor bb007 to enrich for T cells with a memory-like phenotype. In preclinical experiments, bb2121 and bb21217 both eliminated an initial tumor in mice; however, when rechallenged with a second tumor in the same mouse, only bb21217 prevented the tumor from growing without retreatment. Additionally, bb21217 also showed higher levels of CCR7 and CD27 compared with bb2121, suggesting higher levels of memory-like T cells, and bb21217 had lower levels of CD57, a marker of T cell exhaustion.

In the phase I study of bb21217, patients were treated with 150 x 10

(n = 6) CAR+ T cells in an initial dose escalation stage. An expansion cohort was opened to further explore the 300 x 10

doses (n = 6), with the latter selected for further investigation. Lymphodepleting chemotherapy was given with fludarabine at 30 mg/m2&nbsp;and cyclophosphamide at 300 mg/m

on days -5, -4, and -3 prior to infusion.

Across the study, 41 patients underwent leukapheresis, with 1 withdrawing and 2 receiving the infusion after the data cutoff. There was a 100% manufacturing success rate, although 3 patients were required to undergo remanufacturing prior to treatment. Patients were allowed to receive bridging therapy during the manufacturing process.

"[Time from leukapheresis to infusion] was about 4 to 5 weeks, which is standard for most of these targeted CAR T cells," said Berdeja. "Bridging therapy was left up to the individual investigator but I suspect that about half if not two-thirds of patients had bridging therapy."

The median age of patients enrolled in the study was 62 years (range, 33-74), and the median time since diagnosis was 5.5 years. Most patients had an ECOG performance status of 1 (63%) and an ISS stage of I (29%). A third of patients (34%) had high-risk cytogenetics and the median number of prior regimens received was 6 (range, 3-17). Ninety-five percent of patients had received prior proteasome inhibitors, IMiDs, and an anti-CD38 antibody. Eighty-two percent of patients had received 1 or more prior autologous stem cell transplants.

The median follow-up for patients in the 300 x 106 and 450 x 106&nbsp;doses was 4.0 and 3.3 months, respectively. At these early assessments, the ORR in the 300 x 106&nbsp;dose arm was 43%, which included a VGPR rate of 29% and a partial response (PR) rate of 14%. However, Berdeja warned that with the short follow up, these numbers were misleading, as some patients were not included in the analysis.

"Many of these patients had not reached 2 assessments to have a confirmed response and were left off the overall response for these percentages, especially for the 450 group," he said. "As is expected with CAR T cells, the responses will deepen over time."

For patients treated with the 450 x 106 dose, the ORR was 57% and was composed of a PR rate of 14%, a VGPR rate of 29%, and an sCR/CR rate of 14%. None of the responding patients had progressed at the time of the data cutoff in September 2019.

The MRD-negative rate was 94% across the full study, with just 1 patient not achieving negative status at the assessment in the 300 x 106 dose arm. At 6 months, CAR T cells continued to be detectable for 8 of 10 patients (80%). Although the numbers were small, at month 12 bb21217 was detectable in 2 of 4 patients (50%). Of the 2 patients with 18 months of follow up, both still had detectable levels of bb21217 (100%).

"bb21217 drug product is enriched for memory-like T cells, which are associated with robust CAR T cell expansion and less disease progression at month 6," said Berdeja. &ldquo;Long-term CAR T-cell persistence was observed in 8 of 10 evaluable patients at month 6 and 2 of 2 at month 18.&rdquo;

All-grade cytokine release syndrome (CRS) occurred in 66% of patients, most of which was grade 1 or 2 in severity; however, 1 patient had a grade 5 CRS event at the 450 x 106 dose. The median time to onset of CRS was 3 days and the median duration of CRS was 4 days. Neurotoxicity occurred in 24% of patients. There were 2 grade 3 events and 1 grade 4 event, with the remainder being grade 1 or 2. The median time to neurotoxicity onset was 7 days.

Grade 3/4 treatment-emergent adverse events (AEs) included neutropenia (82%), leukopenia (55%), thrombocytopenia (55%), anemia (50%), lymphopenia (34%), hypophosphatemia (21%), infection (18%), hyponatremia (13%), and febrile neutropenia (11%). Half of patients had a serious AE (50%), and 95% had at least 1 grade 3/4 AE.

The expansion arm of the CRB-402 study continues to enroll participants for the 450 x 106 dose of bb21217. The planned enrollment for the study is 74 patients (NCT03274219).

Berdeja JG, Alsina M, Shah N, et al. Updated results from an ongoing phase 1 clinical study of bb21217 anti-BCMA CAR T cell therapy. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 927. bit.ly/35bET49.

Articles

In the phase I CRB-402 study, patients with heavily pretreated relapsed/refractory multiple myeloma and minimal residual disease negativity had very good partial responses to the anti-BCMA CAR T cell therapy bb21217, according to updated results presented at the 2019 American Society of Hematology Annual Meeting.<br />
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Impressive Results Continue With Updated Data on bb21217 in Multiple Myeloma

Patients with primary or secondary myelofibrosis who developed resistance to ruxolitinib in the frontline setting, showed clinically meaningful spleen responses and improvements in symptoms with the addition of navitoclax to ruxolitinib (Jakafi), according to findings from a phase II study presented at the 2019 ASH Annual Meeting.

In the single-arm study, spleen volume response of &ge;35% (SVR35) was achieved by 30% of patients at week 24. Additionally, 53% of patients had resolution of palpable splenomegaly. Sixty-five percent of patients experienced a reduction in symptoms, and 35% of patients experienced a &ge;50% reduction in total symptom score (TSS).

"With the addition of navitoclax to ruxolitinib, we were able to observe that there are meaningful spleen responses and improvements in symptom scores," Jacqueline S. Garcia, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, said during a presentation of the findings. "The addition of navitoclax overcomes resistance in patients with uncontrolled myelofibrosis, despite prior prolonged ruxolitinib exposure."

Navitoclax is a small molecule inhibitor of BCLXL, BCL2, and BCLW, which has shown signs of activity in myeloproliferative neoplasm cell lines, including in myelofibrosis. In preclinical models, the combination of JAK2, BCLXL, and BCL2 inhibition was able to synergistically overcome JAK2 mutations and resistance to JAK2 inhibitors. &nbsp;

The phase II study enrolled 34 patients with primary myelofibrosis (n = 16), post-essential thrombocythemia myelofibrosis (n = 5), and post-polycythemia vera myelofibrosis (n = 13). All patients had received ruxolitinib for &ge;12 weeks prior to first dose of navitoclax, with no wash out period prior to the start of the trial. The dose of navitoclax was escalated from 50 mg daily to 300 mg daily over the course of the study.

Of those available for baseline testing, more than half had high molecular risk (52%). The most common mutations identified were JAK2 (79%) and CALR (21%). Overall, 47% of patients at high-risk had 2 or more mutations. The duration of prior ruxolitinib therapy was 21 months (range, 4-71) and the baseline spleen volume was 1665 cm

The best achieved SVR35 was 43% for the combination. Additionally, 25% of patients saw a reduction in bone marrow fibrosis compared with baseline. There was a 1 grade reduction for 13% of patients and a 2 grade improvement for 13% of patients.

The mean white blood cell count at week 24 was 25.8 x 10

/L. Two patients entered the study with transplant dependence, with 1 becoming transplant independent following the addition of navitoclax. Seven patients entered the study receiving &ge;1 unit of packed red blood cells within the past 12 weeks. Of these patients, 57% were transplant-free for &ge;12 weeks following treatment with the combination. Platelet counts stabilized during the study, going from 232 x 10

"Although very early transient thrombocytopenia was observed immediately after dosing, as expected, it was manageable with a slow weekly dosing ramp up," said Garcia. "The time frame of the 8-week nadir is similar to what we initially observed with ruxolitinib alone."

The median duration of navitoclax treatment was 330 days, and 68% were able to achieve the maximum tolerated dose of 300 mg. Most patients entered the trial on ruxolitinib doses >10 mg twice daily (BID) but most were able to reduce their dose to 10 mg BID during the study (88%).

A quarter of patients discontinued navitoclax during the study (27%), due to adverse events (AEs; 9%), progressive disease (6%), and other causes (12%). Grade &ge;3 AEs of any cause were experienced by 79% of patients receiving the combination. The most common grade &ge;3 AEs were thrombocytopenia (44%), anemia (27%), diarrhea (6%), and vomiting (3%). Eight patients experienced a serious AE (24%). There was 1 grade 5 case of pneumonia that was deemed unrelated to navitoclax.

The phase II study is still ongoing to further assess navitoclax alone or in combination with ruxolitinib for patients with myelofibrosis (NCT03222609). Additionally, outside of the United States, an expanded access program is available to gain access to navitoclax (NCT03592576).

Harrison CN, Garcia JS, Mesa JA, et al. Results from a phase 2 study of navitoclax in combination with ruxolitinib in patients with primary or secondary myelofibrosis. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 671. bit.ly/343YuBX.

Patients with primary or secondary myelofibrosis who developed resistance to ruxolitinib in the frontline setting, showed clinically meaningful spleen responses and improvements in symptoms with the addition of navitoclax to ruxolitinib, according to findings from a phase II study presented at the 2019 ASH Annual Meeting.

Navitoclax Shows Activity in Ruxolitinib-Resistant Patients With Myelofibrosis

An extended media overall survival (OS) of 9.9 months was achieved with CC-486 maintenance treatment compared with placebo for older patients with acute myeloid leukemia (AML) in first remission, according to findings from the phase III QUAZAR AML-001 trial presented at the 2019 American Society of Hematology (ASH) Annual Meeting.

After a median follow-up of 41.2 months, the median OS with CC-486 was 24.7 months (95% CI, 18.7-30.5) compared with 14.8 months for placebo (95% CI, 11.7-17.6), representing a 31% reduction in the risk of death with the hypomethylating agent (HR, 0.69; 95% CI, 0.55-0.86; P&nbsp;= .0009). The median relapse-free survival (RFS) was 4.8 months with placebo compared with 10.3 months for CC-486 (HR, 0.65; 95% CI, 0.52-0.81;&nbsp;P&nbsp;= .0001).

"Based on the positive results of this landmark trial, we hope that maintenance therapy with CC-486 represents a new potential therapeutic standard for patients aged 55 or older with AML in first remission," Andrew H. Wei, MBBS, PhD, from the Alfred Hospital and Monash University, Melbourne, Australia, said during a presentation of the results. "Maintenance studies have been undertaken for the last 30 years and to date no particular therapy has been shown to improve overall survival."

CC-486 has a distinct pharmacokinetic and pharmacodynamic profile from injected azacitidine. Earlier studies have shown the agent to be tolerable with efficacious, even in patients who have progressed on prior azacitidine injections. The oral dosing of the drug is felt to provide better drug exposure, in addition to superior patient convenience, which potentially prolongs therapeutic activity, Wei said.

In the phase III trial, 472 patients were enrolled within 4 months of complete remission (CR) or CR with incomplete hematologic recovery (CRi). Patients were evenly randomized to receive therapy with daily CC-486 (n = 238) or placebo (n = 234). CC-486 was administered daily for 14 days followed by 14 days off therapy. If a CR/CRi was not maintained, CC-486 dose could be escalated to 21 days on drug with 7 days of rest.

The median age of patients was 68 years, with over two-thirds &ge;65 years. The most common ECOG performance scores were 0 (47% to 49%) and 1 (42% to 45%). Most patients had de novo AML (approximately 90%) and most had intermediate cytogenetic risk (approximately 86%).

In the CC-486 groups, the best responses to prior therapy consisted of CR for 79% of patients and CRi for 21%. In the placebo arm, the best responses were CR for 84% of patients and CRi for 16%. Across both groups, approximately one-fifth of patients had not received consolidation therapy prior to study entry and approximately half of patients tested negative for minimal residual disease.

At 1 year, 47% of patients were free of relapse in the CC-486 arm compared with 29% in the placebo group. Benefits in both RFS and OS were seen across key prognostic AML subgroups, Wei said.

The median treatment duration was 12 cycles with CC-486 compared with 6 in the placebo group, which speaks to the tolerability of the agent, Wei said. "One measure of safety is the number of cycles the patient can tolerate," he said. "Some patients in the CC-486 arm received up to 80 cycles of treatment.

The safety profile was consistent with injectable azacitidine, with infrequent treatment discontinuation related to adverse events (AEs). There were no treatment-related deaths. The most common all-grade AEs with CC-486 were gastrointestinal in nature, including nausea (65%), vomiting (60%), diarrhea (50%), and constipation (39%). The most common grade 3/4 AEs in the CC-486 and placebo groups, respectively, were neutropenia (41% vs 24%), thrombocytopenia (23% vs 22%), anemia (14% vs 13%), diarrhea (5% vs 1%), vomiting (3% vs 0%), fatigue (3% vs 1%), and nausea (3% vs 0.4%).

"Although the gastrointestinal events seem high here, it was because this was a placebo-controlled study, so we did not know which treatment patients were receiving initially. When people get azacitidine-like therapy, they do get gastrointestinal side effects," said Wei. "In subsequent cycles, patients were put on prophylactic therapy, so these events were significantly reduced beyond cycle 2."

Topline results from the QUAZAR study were announced in September by the manufacturer of the drug, Celgene. In this statement, the company announced plans to submit a regularly application for CC-486 in the first quarter of 2020.

Wei AH, Dӧhner H, Pocock C, et al. The QUAZAR AML-001 Maintenance Trial: Results of a Phase III International, Randomized, Double-Blind, Placebo-Controlled Study of CC-486 in Patients with Acute Myeloid Leukemia (AML) in First Remission. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract LBA3.

An extended media overall survival of 9.9 months was achieved with CC-486 maintenance treatment compared with placebo for older patients with acute myeloid leukemia in first remission, according to findings from the phase III QUAZAR AML-001 trial presented at the 2019 American Society of Hematology Annual Meeting.<br />
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CC-486 Maintenance Extends OS in Older Patients With Acute Myeloid Leukemia

Patients with relapsed/refractory mantle cell lymphoma (MCL) experienced a 67% complete remission (CR) rate and an objective response rate (ORR) of 93% after treatment with the anti-CD19 CAR T-cell therapy KTE-X19, according to findings from the phase II ZUMA-2 study presented at the 2019 American Society of Hematology (ASH) Annual Meeting.

The median follow-up at the analysis was 12.3 months (range, 7.0-32.3), with 47% of patients having followed for &ge;24 months. Forty percent of patients who initially had a partial remission (PR) or stable disease transitioned to CRs, with a median time CR of 3 months (range, 0.9-9.3). There were no cases of grade 5 cytokine release syndrome (CRS) or neurotoxicity.

Based on findings from the ZUMA-2 trial, Kite and Gilead plan to submit a biologics license application to the FDA within the next few weeks for KTE-X19 in relapsed/refractory MCL. A marketing authorization application will also be submitted to the European Medicines Agency (EMA) in the first quarter of 2020.

"KTE-X19, in a single infusion, demonstrates high rates of durable responses in relapsed/refractory mantle cell lymphoma," Michael L. Wang, MD, the University of Texas MD Anderson Cancer Center, said during a presentation of the results. "The 93% overall response rate, which includes a 67% CR rate, is the highest reported rate of disease response in patients with prior BTK inhibitor failure."

KTE-X19 consists of an anti-CD19 single-chain variable fragment with a CD3 zeta T cell activation domain and a CD28 signaling domain. During the manufacturing process, circulating tumor cells are separated from autologous immune cells, which differentiates KTE-X19 from axicabtagene ciloleucel (Yescarta), Wang noted.

Overall, 74 patients were enrolled and underwent leukapheresis in the study, with 5 patients not receiving the therapy due to manufacturing failures (n = 3) or death from progressive disease (n = 2). Overall, 69 patients went on to receive conditioning chemotherapy with 68 received KTE-X19. The primary efficacy analysis presented at ASH was conducted on the first 60 patients enrolled in the study. Overall, KTE-X19 was effectively manufactured for 96% of patients and administered to 92%. The median time from leukapheresis to delivery of KTE-X19 was 16 days.

"The efficacy, reliable and rapid manufacturing, and manageable toxicities identify an important and promising role for KTE-X19 in treating patients with relapsed/refractory mantle cell lymphoma who have an urgent unmet medical need," said Wang.

During the manufacturing process, patients in the study were allowed to receive bridging therapy for progressive disease at the investigator&rsquo;s discretion. This could include ibrutinib, acalabrutinib, or dexamethasone but not chemotherapy. Beginning 5 days prior to T cell infusion, patients received 3 consecutive days of conditioning chemotherapy with fludarabine at 30 mg/m

The median age of patients enrolled in the study was 65 years, with 57% aged &ge;65 years. Most patients had stage IV disease (85%) and 56% were intermediate or high-risk. The Ki-67 proliferation index was &ge;50% in 69% of patients and 17% had TP53 mutations. Bone marrow involvement was found in 54% of patients, and 56% had extranodal disease. The most common morphologies were classical (59%), blastoid (25%), and pleomorphic (6%).

Prior to study entry, patients had received a median of 3 prior therapies, with that majority having 3 or more treatments (81%). Almost all patients had received prior anthracycline or bendamustine and 100% of patients had received a prior anti-CD20 antibody. BTK inhibitors had been received by 100% of patients prior to study entry. Thirty-seven percent of patients received bridging therapy, most commonly with ibrutinib (21%). Of those who received bridging therapy, most had higher disease burden prior to infusion of the CAR T cells compared with baseline (92%).

"Bridging therapy was not intended to be curative, but simply to keep the lymphoma stable during manufacturing. The majority had increased tumor load instead of decreased tumor load," Wang said.

At the time of the analysis, the median duration of response had not yet been reached. Of those reaching a CR, 78% remained in remission at the time of the analysis. For the first 28 patients treated on the trial, the median follow-up was 27.0 months. In these patients, 43% of responders remained in remission, suggesting high durability of response with a plateau in the curve.

The median progression-free survival (PFS) was not yet reached. The 12-month PFS rate was 61%, with a tail on the curve (95% CI, 45%-74%). Additionally, the median overall survival (OS) was also not reached, with a 12-month OS rate of 83% (95% CI, 71%-91%).

"I have been treating mantle cell lymphoma for 20 years, and every time I see a plateau in the curve, I get very excited. But the follow-up is very short. We are still cautiously optimistic," said Wang.

As a single-arm study, Wang cited historical numbers for context. Overall, a typical ORR in patients with MCL who progress on BTK inhibition is 25% to 42%, he said. Additionally, few patients in this setting go on to receive potentially curative allogeneic stem cell transplant. The median OS for these patients is between 6 and 10 months. For the ZUMA-2 trial, at the 12.3-month analysis, the low end of the 95% CI for OS with KTE-X19 was 24 months.

The most frequent treatment-emergent adverse event (TEAEs) of any grade were pyrexia (94%), neutropenia (87%), thrombocytopenia (74%), anemia (68%), and hypotension (51%). Grade 4 TEAEs included neutropenia (69%), thrombocytopenia (35%), hypoxia (9%), and hypotension (3%). There were 2 grade 5 AEs: the first was pneumonia related to the conditioning therapy and the second was staphylococcal bacteremia due to post-conditioning therapy and the CAR T cell infusion.

All grade CRS occurred in 91% of patients, which was grade &ge;3 in severity for 15% of patients. The majority of pyrexia, hypotension, and hypoxia events seen in the study were related to CRS. Management for CRS included tocilizumab (59%) or corticosteroids (22%). The median time to onset was 2 days and the median duration was 11 days. All events resolved.

All grade neurotoxicity was experienced by 63% of patients treated with KTE-X19, with 31% having a grade &ge;3 event. The most common symptoms were tremor (35%), encephalopathy (31%), and confusion (21%). This AE was managed with tocilizumab (26%) and corticosteroids (38%) and the median time to onset was 7 days with a median duration of 12 days.

There was one case of grade 4 cerebral edema in the study that was confirmed using MRI of the brain. Following intubation, this patient was treated with aggressive therapy, including tocilizumab, siltuximab, high-dose steroids, intrathecal Ara C plus dexamethasone, mannitol, ventriculostomy, and IV rabbit anti-thymocyte globulin (ATG). The neurotoxicity fully resolved for this individual and the CR had remained ongoing for 24 months at the data cutoff.

"This is the first reported use of ATG in treating CAR T cell-related toxicities," said Wang. Anecdotally, he added that he had seen this patient recently, and that they remained in CR. Making the duration of response 30+ months.

In addition to the upcoming BLA submission, KTE-X19 has received a breakthrough therapy designation from the FDA and a prime medicines (PRIME) designation from the EMA, both based on findings from the ZUMA-2 trial.

Wang ML, Munoz J, Goy A, et al. KTE-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, in Patients (Pts) With Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL): Results of the Phase 2 ZUMA-2 Study. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract 754.

Patients with relapsed/refractory mantle cell lymphoma experienced a 67% complete remission rate and an objective response rate of 93% after treatment with the anti-CD19 CAR T-cell therapy KTE-X19, according to findings from the phase II ZUMA-2 study presented at the 2019 American Society of Hematology ASH Annual Meeting.

Silas Inman | Authors

Articles

Impressive Results Continue With Updated Data on bb21217 in Multiple Myeloma

Navitoclax Shows Activity in Ruxolitinib-Resistant Patients With Myelofibrosis

CC-486 Maintenance Extends OS in Older Patients With Acute Myeloid Leukemia

FDA Submission for KTE-X19 Planned After High CR Rates Were Observed in MCL