Zella 201: A Biomarker-Guided Phase II Study of Alvocidib Followed By Cytarabine and Mitoxantrone in MCL-1 Dependent Relapsed/Refractory Acute Myeloid Leukemia (AML)

Abstract

Background Multiple studies have shown the clinical activity of alvocidib followed by cytarabine and mitoxantrone in newly diagnosed and relapsed/refractory (R/R) AML. Alvocidib's anti-leukemic pharmacologic activity appears to be predominantly due to the inhibition of transcriptional regulator, CDK9, resulting in suppression of CDK9-regulated genes, such as the BCL-2 family member, MCL-1. Pre-treatment bone marrow samples from newly diagnosed AML patients revealed an increased sensitivity to alvocidib in those with MCL-1 dependence of ≥40% as measured by a BH3 profiling biomarker assay (J Clin Oncol 33, 2015 suppl; 7062). Thus, we hypothesized that alvocidib, followed by cytarabine and mitoxantrone, may be preferentially active in those with MCL-1 dependence (≥ 40%). Here, the findings from stage 1 of the Zella 201 trial in which this biomarker assay is used to select for patients with MCL-1 dependence, are reported. Aims To evaluate the efficacy and safety of alvocidib, in combination with cytarabine and mitoxantrone, in MCL-1 dependent R/R AML patients. Methods The key eligibility criteria were: ages 18-65 years; refractory to 1-2 cycles of induction therapy, or in first relapse AML with complete remission (CR) duration ≤ 2 years; ≥ 40% myeloblast MCL-1 dependency determined by BH3 profiling; ECOG PS 0-2; and no major organ dysfunction. Patients who received prior allogeneic stem cell transplant (alloSCT) were eligible, if it was greater than two months after SCT and there was no active GVHD. Treatment consisted of alvocidib 30 mg/m2 as a 30-minute IV bolus followed by 60 mg/m2 over 4 hours on Days 1-3, cytarabine 667 mg/m2/day by continuous IV infusion days 6-8, and mitoxantrone 40 mg/m2 IV on day 9 starting 12 hours after completing cytarabine. Up to 3 additional cycles of the same regimen (with or without mitoxantrone) were permittedin responders. The primary endpoint was the rate of CR+CR with incomplete recovery (CRi). Stage I was determined to be positive if ≥13 CRs were seenin the first 23 evaluable patients. Key secondary endpoints were overall survival, event-freesurvival, the combinedresponse rate and safety assessed by adverse events and laboratory results. Results A total of 163 patients were screened, of which 47 (29%) were determined to be MCL-1 dependent. Of these, 25 patients were enrolledin Stage 1 (Table 1), with 21 evaluable for response. Median MCL-1 dependence score was 55% (range: 41-98%). Of the 21 evaluable patients, 11 (52%) were refractory to frontline therapy (resistant disease or CR < 90d). The overall CR/CRi rate in evaluable patients was 62% (13/21) meeting the primary endpoint of stage 1. Seven out of 11 (64%) patients with primary refractory disease achieved a CR and five of these patients proceeded to an alloSCT. Overall, 10 patients received a post-study alloSCT. The most common NCI CTCAE ≥Grade 3treatment-emergent nonhematologic AEs noted in >1 patient in the safety population (n=25) were tumor lysis syndrome (20% Grade 3, 8% Grade 4); diarrhea (24% Grade 3); increased AST (12% Grade 3, 8% Grade 4), sepsis (16% Grade 5, 4% Grade 4); and peripheral edema, (8% Grade 3). To date, overall 30- and 60-day mortality rates were 16% and 20%, respectively, due to sepsis (n=4), and mitral valve rupture (n=1). Conclusion Our findings indicate that alvocidib given beforecytarabine and mitoxantrone in MCL-1-dependent AML has clinical activity, particularly in those refractory to frontline therapy. Given these findings, stage 2 of the Zella 201 trial has been initiated,randomizing patients to alvocidib, cytarabine, and mitoxantrone versus cytarabine and mitoxantrone alone in MCL-1 dependent R/R AML. Furthermore, a Phase Ib study of alvocidib followed by 7+3 induction in newly diagnosed AML (Zella 101) is being conducted. Disclosures Zeidner: Rafael Pharmaceuticals: Other: Travel Fees; Takeda: Other: Travel fees, Research Funding; Merck: Research Funding; Asystbio Laboratories: Consultancy; Tolero: Honoraria, Other: Travel Fees, Research Funding; Celgene: Honoraria. Lin:Jazz Pharmaceuticals: Honoraria. Wang:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Amgen: Consultancy. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Montesinos:Daiichi Sankyo: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Anthony:Tolero Pharmaceuticals, Inc: Employment. Bearss:Tolero Pharmaceuticals, Inc: Employment.

Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia

“…We defined the criteria of MCL-1 dependence as a priming threshold of >30%. Although there are no uniform criteria for defining MCL-1 dependence, the 30% threshold is consistent with our revised eligibility criteria for a randomized phase 2 trial of cytarabine plus mitoxantrone with or without alvocidib in patients with relapsed/refractory MCL-1 dependent AML (45). We did not appreciate any significant differences in response to alvocidib in patients with or without MCL-1 dependence though this In conclusion, alvocidib administration prior to 7+3 induction is tolerable, feasible, and showed encouraging clinical activity in newly diagnosed AML with non-favorable risk cytogenetics.…”

Heterogeneity in refractory acute myeloid leukemia

“…This drug has already successfully been used in combination for the treatment of both newly diagnosed high-risk and Ref/relapsed AML patients (44)(45)(46)(47), with complete remission rates often superior to 7 + 3. Biomarker-based clinical trials of this combination are now ongoing (48).…”

Emerging Therapies for Acute Myelogenus Leukemia Patients Targeting Apoptosis and Mitochondrial Metabolism

“…The only difference observed was the higher complete remission rates observed among patients treated with alvocidib [122,123]. In a recent phase II trial, that used BH3 profiling as laboratory support to predict response to therapy, 17 patients with refractory/relapsing AML and a median MCL-1 dependency of 61% (measured by the BH3 profiling assay) received treatment with alvocidib administered before cytarabine and mitoxantrone [124]. A complete remission rate with incomplete hematologic recovery rate of 59% was observed; 75% of AML patients with refractory AML achieved CR and 50% of them were able to proceed to allogeneic stem cell transplantation [124].…”

“…In a recent phase II trial, that used BH3 profiling as laboratory support to predict response to therapy, 17 patients with refractory/relapsing AML and a median MCL-1 dependency of 61% (measured by the BH3 profiling assay) received treatment with alvocidib administered before cytarabine and mitoxantrone [124]. A complete remission rate with incomplete hematologic recovery rate of 59% was observed; 75% of AML patients with refractory AML achieved CR and 50% of them were able to proceed to allogeneic stem cell transplantation [124]. A more recent update of this trial presented at the December 2018 ASH Meeting showed that among 163 AML patients screened, 29% were shown to be MCL-dependent; of these, 21 of the 25 enrolled patients were evaluable for response: 52% of these patients were resistant to standard frontline therapy; 62% of these patients showed a CR or Cri to therapy with alvocidib, cytarabine and mitoxantrone [125].…”

“…A complete remission rate with incomplete hematologic recovery rate of 59% was observed; 75% of AML patients with refractory AML achieved CR and 50% of them were able to proceed to allogeneic stem cell transplantation [124]. A more recent update of this trial presented at the December 2018 ASH Meeting showed that among 163 AML patients screened, 29% were shown to be MCL-dependent; of these, 21 of the 25 enrolled patients were evaluable for response: 52% of these patients were resistant to standard frontline therapy; 62% of these patients showed a CR or Cri to therapy with alvocidib, cytarabine and mitoxantrone [125]. Given these findings, stage 2 of this trial was initiated, randomizing the patients to alvocidib, cytarabine and mitoxantrone versus cytarabine, mitoxantrone alone in MCL-1-dependent refractory AMLs [125].…”