-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

1018 Safety of Palbociclib in Combination with Chemotherapy in Pediatric and Young Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia and Lymphoma: A Children’s Oncology Group Pilot Study

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation: Poster I
Hematology Disease Topics & Pathways:
Leukemia, ALL, Diseases, Lymphoma (any), Non-Biological, Therapies, chemotherapy, Pediatric, Young Adult, Lymphoid Malignancies, Study Population
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Elizabeth A. Raetz, MD1, David T. Teachey, MD2, Charles Minard, PhD3*, Xiaowei Liu, MS4*, Robin Norris, MD, MS, MPH5, Joel Reid, PhD6*, Thalia Beeles, MPh4*, Lia Gore, MD7, Elizabeth Fox, MD8*, Mignon L. Loh, MD9, Brenda J. Weigel, MD, MSc10* and William L. Carroll, MD1

1Department of Pediatrics and Perlmutter Cancer Center, NYU Langone Health, New York, NY
2Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA
3Dan L. Duncan Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX
4Children's Oncology Group, Monrovia, CA
5Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
6Mayo Clinic, Rochester, MN
7Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado and Children’s Hospital, Aurora, CO
8St. Jude Children's Research Hospital, Memphis, TN
9Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of California Benioff Children’s Hospital, San Francisco, CA
10University of Minnesota, Minneapolis, MN

Background: Despite improvements in outcomes for children with B- and T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma (B-ALL, T-ALL, B-LLy and T-LLy), the outcome of patients with primary resistant or relapsed disease remains very poor, particularly for children with second or greater relapses and with T-cell disease. Deregulation of cell cycle machinery is essential for both the induction and progression of ALL (Sicinska et al. Cancer Cell 4:451-61, 2003). Additionally, targeting cell cycle regulators CDK4 and 6 efficiently suppresses ALL growth and disease progression in vivo (Sawei et al. Cancer Cell 22:452-65, 2012) and this effect is augmented by conventional chemotherapy. These data provided the rationale for investigating the CDK4/6 inhibitor palbociclib in relapsed/refractory ALL and LLy. Preliminary results from the ongoing Children’s Oncology Group (COG) AINV18P1 trial are reported.

Methods: Patients aged 1-30 years with first or greater isolated or combined marrow relapses of T-ALL or T-LLy and second or greater relapses of B-ALL or B-LLy are eligible for COG AINV18P1 (NCT03792256). Patients with refractory disease with at least 2 prior induction attempts or first relapse refractory to at least one prior re-induction attempt are also eligible. This is a 2-part study conducted at selected COG sites. In Part 1 of the study (dose determination), palbociclib was administered orally once daily for 21 consecutive days, first as a single agent (days 1-3) and subsequently in combination with 4-drug re-induction chemotherapy (Table 1). Study treatment consisted of a single cycle of therapy. A starting palbociclib dose of 50 mg/m2/dose was explored with one dose de-escalation (35 mg/m2/dose) using the rolling six design to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Part 2 (expansion cohort) is accruing 6 additional patients (pts) at the MTD for further assessment of the safety and feasibility of combination therapy. Dose-limiting toxicities (DLTs), defined as hematologic and non-hematologic toxicities exceeding baseline toxicities observed with re-induction chemotherapy alone, are assessed throughout the treatment cycle. The primary aims of the study are safety, determination of the MTD/RP2D and assessment of palbociclib pharmacokinetics (PK). Secondary aims are assessment of the biological and preliminary clinical activity of combination therapy in this patient population.

Results: As of June 30, 2020, 8 pts have enrolled; 6 in Part 1 and 2 in Part 2. All 6 pts in Part 1 completed one full cycle (32 days) of protocol therapy. The median (range) age of pts is 10 (6-21) years and 62% are male (Table 2). Three pts had T-ALL, 4 B-ALL and 1 T-LLy. Pts received a median (range) of 2 (1-6) prior chemotherapy regimens and 2 pts underwent prior allogeneic stem cell transplant. All 6 pts in Part 1 experienced grade 3-4 toxicities, most commonly hematologic: anemia (3 pts), neutropenia (5 pts) and thrombocytopenia (4 pts). Three pts had grade 3 infections and one pt had grade 3 hyperbilirubinemia, which resolved. No hematologic or non-hematologic DLTs were observed at the 50 mg/m2/dose of palbociclib in Part 1 and accrual to the expansion phase of the trial at this dose continues. PK and pharmacodynamic studies assessing cell cycle inhibition are also ongoing.

Conclusions: Palbociclib in combination with 4-drug re-induction chemotherapy is safe and well tolerated in children and young adults with relapsed/refractory ALL and LLy. Further assessment of the feasibility and activity of combination therapy is ongoing in the expansion phase of this trial.

Disclosures: Raetz: Celgene: Other: DSMB member; Pfizer: Other: Institutional research funding. Teachey: La Roche: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Sobi: Consultancy. Norris: Merck: Other: Travel funding. Gore: Amgen, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Loh: Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding.

OffLabel Disclosure: This study includes off-label use of palbociclib in children and young adults with relapsed/refractory acute lymphoblastic leukemia and lymphoblastic lymphoma.

*signifies non-member of ASH