Accelerating Drug Development in Pediatric Cancer: A Novel Phase I Study Design of Venetoclax in Relapsed/Refractory Malignancies

Figures & data

Figure 1. Mechanism of action of venetoclax.

MOMP: Mitochondrial outer membrane permeabilization.

Adapted from Cancer Discovery, 2016, 6(10), 1106–1117, Konopleva M, Pollyea DA, Potluri J et al. Efficacy and biological correlates of response in a Phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia, with permission from AACR [6].

Table 1. Mechanism-based selection of pediatric tumor types.

Pediatric cancer type	BCL-2 overexpression	Cell line response to venetoclax	Murine xenograft response to venetoclax	Clinical response to venetoclax in adults
ALL	– Upregulation by the MLL–AF4 fusion protein [1,14,15], TCF3–HLF [16] and hypodiploid ALL [17]	– Responses in T-ALL, MLL-ALL and hypodiploid ALL cell lines, and synergy when combined with chemotherapy [14,17–19]	– MLL-ALL: 3/6 ORR (1 maintained CR, 1 CR and 1 PR); B-cell precursor ALL: 3/9 ORR (2 CR and 1 PR) [20] – Delayed progression in 11/19 xenografts [21] – Substantial reduction in leukemia cells in hypodiploid ALL xenografts [17]	– Not yet tested
AML	– High BCL-2 protein levels in cell lines and patient samples [9,10]	– 14/24 AML cell lines sensitive to venetoclax [22]; quick and potent cell-killing activity [10] – Synergy when combined with 5-azacitidine [9,23]	– Markedly prolonged overall survival and significantly reduced tumor burden [10]	– Venetoclax monotherapy (800 mg QD): 19% ORR [6] – Venetoclax (600 mg QD) + LDAC: 64% ORR [12] – Venetoclax (400, 800 or 1200 mg QD) + HMA: 67% ORR [13]
NHL	– High BCL-2 expression in cell lines [1]	– Broad cell-killing activity demonstrated against a panel of NHL cell lines [1]	– 100% tumor regression when combined with bendamustine and rituximab [1] – Cell-killing activity in DLBCL xenografts [24]	DLBCL subtype: – Venetoclax monotherapy (up to 1200 mg QD): 18% ORR [25] – Venetoclax (50–1200 mg QD) + BR: 41% ORR [26]
Neuroblastoma	– High BCL-2 expression levels in certain cell lines [27–29]	– High sensitivity of cell lines to venetoclax treatment [27]	– Long-term survival in 20% of mice with monotherapy and 60% in combination with cyclophosphamide [28]	– Not tested/not applicable

ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; BR: Bendamustine/rituximab; CR: Complete response; CRi: Complete response with incomplete marrow recovery; DLBCL: Diffuse large B-cell lymphoma; HMA: Hypomethylating agent; LDAC: Low-dose cytarabine; MLL: Mixed lineage leukemia; NHL: Non-Hodgkin lymphoma; ORR: Objective response rate; PR: Partial response; QD: Daily; T-ALL: T-cell acute lymphoblastic leukemia.

Figure 2. Two-part study design.

^†The first ten patients will be pediatric patients <18 years of age; a maximum of 20 patients may enroll.

^‡Excluding brain tumors.

^§Potential to de-escalate or escalate.

^¶Must have evidence of BCL-2 expression and includes patients with TCF3-HLF ALL.

ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; NHL: Non-Hodgkin lymphoma; PK: Pharmacokinetic.

Table 2. Venetoclax dose ramp-up in patients with hematologic malignancies or lymphomas.

Dose groups	3-day ramp-up to 800-mg adult exposure-equivalent target dose of venetoclax
	Day 1, mg	Day 2, mg	Day 3 and onward, mg
Age: – Newborn to <1 month – 1 to <3 months – 3 to <6 months – 6 months to <1 year – 1 to <2 years	2.5 5 10 25 40	5 10 25 50 80	10 25 50 100 150
Weight: – 10 to <20 kg – 20 to <30 kg – 30 to <45 kg – ≥45 kg	50 80 120 200	120 170 250 400	250 350 500 800

Table 3. Venetoclax dose ramp-up in patients with solid tumors.

Dose groups	2-day ramp-up to 800-mg adult exposure-equivalent target dose of venetoclax
	Day 1, mg	Day 2 and onward, mg
Age: – Newborn to <1 month – 1 to <3 months – 3 to <6 months – 6 months to <1 year – 1 to <2 years	5 10 25 50 80	10 25 50 100 150
Weight: – 10 to <20 kg – 20 to <30 kg – 30 to <45 kg – ≥45 kg	120 170 250 400	250 350 500 800

Figure 3. Study overview.

(A) Patients with ALL, AML and NHL. (B) Patients with neuroblastoma and other solid tumors.

^†Longer durations of therapy may be allowed.

ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; IV: Intravenous; NHL: Non-Hodgkin lymphoma; TLS: Tumor lysis syndrome.

Table 4. Allowed chemotherapy regimens in combination with venetoclax for each tumor type.

Tumor type	Allowed chemotherapy regimens
ALL	Dexamethasone and/or vincristine and/or pegasparaginase OR Cytarabine and/or etoposide and/or pegasparaginase
ALL with Philadelphia chromosome or with an ABL class targetable fusion	Tyrosine kinase inhibitor + above regimens for ALL
AML	Low-dose cytarabine OR Hypomethylating agents: azacitidine/decitabine
NHL	Rituximab and/or dexamethasone and/or vincristine
Neuroblastoma	Cyclophosphamide and/or topotecan
Other tumors	Cyclophosphamide and/or topotecan

ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; NHL: Non-Hodgkin lymphoma.

Table 5. Key inclusion and exclusion criteria.

Inclusion criteria

Exclusion criteria

– Adequate hepatic and renal function (aspartate aminotransferase and alanine aminotransferase must be <3 × institutional upper limit of normal and total bilirubin must be ≤1.5 × institutional upper limit of normal) – Normal creatinine for age or calculated creatinine clearance ≥60 ml/min/1.73 m^2, Lansky ≥50 (if ≤16 years of age), or Karnofsky ≥50 (if >16 years of age) – In Part 1, patients must have relapsed/refractory cancer without available curative treatment options – Patients with solid tumors (with the exception of neuroblastoma) are required to have adequate bone marrow function as defined by ANC ≥1000 cells/μl and platelets >75,000 cells/μl (with transfusion independence defined as not receiving platelet transfusion within 7 days prior to enrollment) – In Part 2, patients must have relapsed/refractory ALL, AML, NHL or neuroblastoma with histologically confirmed diagnosis – For enrollment in the fifth cohort of Part 2, patients with other tumors must have evidence of BCL-2 expression (determined locally, preferably utilizing immunohistochemistry) or must have TCF3–HLF ALL confirmed prior to the end of induction therapy

– Patients with primary brain tumors or disease metastatic to the brain, and patients with leukemia having overt CNS disease (CNS 3 status); due to preclinical data indicating that venetoclax is unlikely to penetrate a mature blood–brain barrier – Patients who have received any of the following prior to the first dose of study drug: biologic agent (i.e., antibodies) within 30 days; CAR T infusion or other cellular therapy within 30 days; anticancer therapy including blinatumomab or chemotherapy, radiation therapy, targeted small-molecule agents, investigational agents within 14 days or 5 half-lives, whichever is shorter; steroid therapy for antineoplastic intent within 5 days; ongoing hydroxyurea (hydroxyurea permitted up to first dose) – Patients who are <100 days post-transplant, or >100 days post-transplant with active graft-versus-host disease, or requiring immunosuppression within 7 days prior to first dose of study drug

ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; ANC: Absolute neutrophil count; CAR: Chimeric antigen receptor; NHL: Non-Hodgkin lymphoma.

Table 6. Efficacy assessment criteria for each tumor type. 

	ALL/AML	NHL	Neuroblastoma	Solid tumors
Criteria	CR: hematologic recovery (ANC ≥500/μl; platelet count ≥75,000/μl) CRi: CR except ANC <500/μl and/or platelets <75,000/μl CRp: CR except platelets <75,000/μl (no transfusions or support by exogenous growth factors) PR: no peripheral blasts, or peripheral blood absolute blast count decreased by ≥50% from baseline SD/resistant disease: criteria for CR, CRi, CRp, PR or progressive disease not met Progressive disease: >50% increase in absolute peripheral or bone marrow Relapse: reappearance of blasts in the blood (unless consistent with regenerating bone marrow) or bone marrow (>5% blasts) or in any extramedullary site after achieving CR	Lugano criteria [50]	International neuroblastoma response criteria [51]	RECIST v1.1 [52]
First assessment	Week 4 (day 22 after initiation)	Week 8
Frequency of assessments	Monthly between week 4 and 12 and then every 12 weeks thereafter, and at any other time point if clinically indicated, including day 8	Week 24 and then every 12 weeks thereafter, and at any other time point if clinically indicated, including week 4

ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; ANC: Absolute neutrophil count; CR: Complete response; CRi: Complete response with incomplete marrow recovery; CRp: CR without platelet recovery; NHL: Non-Hodgkin lymphoma; PR: Partial response; RECIST: Response Evaluation Criteria In Solid Tumors; SD: Stable disease.

Konopleva M , PollyeaDA, PotluriJet al. Efficacy and biological correlates of response in a Phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov.6(10), 1106–1117 (2016).

 PubMed Web of Science ®Google Scholar

Souers AJ , LeversonJD, BoghaertERet al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med.19(2), 202–208 (2013).

 PubMed Web of Science ®Google Scholar

Benito JM , GodfreyL, KojimaKet al. MLL-rearranged acute lymphoblastic leukemias activate BCL-2 through H3K79 methylation and are sensitive to the BCL-2-specific antagonist ABT-199. Cell Rep.13(12), 2715–2727 (2015).

 PubMed Web of Science ®Google Scholar

Ackler S , OleksijewA, ChenJet al. Clearance of systemic hematologic tumors by venetoclax (Abt-199) and navitoclax. Pharmacol. Res. Perspect.3(5), e00178 (2015).

 PubMedGoogle Scholar

de Boer J , YeungJ, ElluJet al. The E2A–HLF oncogenic fusion protein acts through Lmo2 and Bcl-2 to immortalize hematopoietic progenitors. Leukemia25(2), 321–330 (2011).

 PubMed Web of Science ®Google Scholar

Diaz-Flores E , ComeauxEQ, KimKet al. BCL-2, a therapeutic target for high risk hypodiploid B-cell acute lymphoblastic leukemia. Blood128(22), 280 (2016).

 Web of Science ®Google Scholar

Jones L , CarolH, EvansKet al. A review of new agents evaluated against pediatric acute lymphoblastic leukemia by the Pediatric Preclinical Testing Program. Leukemia30(11), 2133–2141 (2016).

 PubMed Web of Science ®Google Scholar

Khaw SL , SuryaniS, EvansKet al. Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia. Blood128(10), 1382–1395 (2016).

 PubMed Web of Science ®Google Scholar

Bogenberger JM , KornblauSM, PierceallWEet al. BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies. Leukemia28(8), 1657–1665 (2014).

 PubMed Web of Science ®Google Scholar

Pan R , HogdalLJ, BenitoJMet al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov.4(3), 362–375 (2014).

 PubMed Web of Science ®Google Scholar

Leverson JD , PhillipsDC, MittenMJet al. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci. Transl. Med.7(279), 279ra40 (2015).

 PubMed Web of Science ®Google Scholar

Bogenberger JM , DelmanD, HansenNet al. Ex vivo activity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignancies. Leuk. Lymphoma56(1), 226–229 (2015).

 PubMed Web of Science ®Google Scholar

Wei A , StricklandSA, RobozGJet al. Phase I/II study of venetoclax with low-dose cytarabine in treatment-naive, elderly patients with acute myeloid leukemia unfit for intensive chemotherapy: 1-year outcomes. Blood130(Suppl. 1), Abstract 890 (2017).

 Google Scholar

DiNardo CD , PollyeaDA, JonasBAet al. Updated safety and efficacy of venetoclax with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood130(Suppl. 1), Abstract 2628 (2017).

 PubMedGoogle Scholar

Li L , PongtornpipatP, TiutanTet al. Synergistic induction of apoptosis in high-risk DLBCL by BCL2 inhibition with ABT-199 combined with pharmacologic loss of MCL1. Leukemia29(8), 1702–1712 (2015).

 PubMed Web of Science ®Google Scholar

Davids MS , RobertsAW, SeymourJFet al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J. Clin. Oncol.35(8), 826–833 (2017).

 PubMed Web of Science ®Google Scholar

Swinnen LJ , FlowersCR, WangDet al. Venetoclax (VEN), bendamustine (B) and rituximab (R) in patients (pts) with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL): final results of a Phase I study. Hematol. Oncol.35(Suppl. S2), Abstract 79 (2017).

 Google Scholar

Bate-Eya LT , den HartogIJ, van der PloegIet al. High efficacy of the BCL-2 inhibitor ABT199 (venetoclax) in BCL-2 high-expressing neuroblastoma cell lines and xenografts and rational for combination with MCL-1 inhibition. Oncotarget7(19), 27946–27958 (2016).

 PubMedGoogle Scholar

Tanos R , KarmaliD, NalluriS, GoldsmithKC. Select Bcl-2 antagonism restores chemotherapy sensitivity in high-risk neuroblastoma. BMC Cancer16, 97 (2016).

 PubMed Web of Science ®Google Scholar

Cheson BD , FisherRI, BarringtonSFet al. Recommendations for initial evaluation, staging and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J. Clin. Oncol.32(27), 3059–3068 (2014).

 PubMed Web of Science ®Google Scholar

Park JR , BagatellR, CohnSLet al. Revisions to the International Neuroblastoma Response Criteria: a consensus statement from the National Cancer Institute Clinical Trials Planning Meeting. J. Clin. Oncol.35(22), 2580–2587 (2017).

 PubMed Web of Science ®Google Scholar

Eisenhauer EA , TherasseP, BogaertsJet al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer45(2), 228–247 (2009).

 PubMed Web of Science ®Google Scholar