PRIMARY OBJECTIVES:
I. The primary objective of the phase 1 part of this trial is to define the schedule of sequential abemaciclib and gemcitabine and recommended phase 2 dose (RP2D) of retinoblastoma positive (Rb\[+ve\]) sarcomas.
II. The primary objective of the phase 2 part of the trial is to define the progression-free survival (PFS) of sequential abemaciclib followed by gemcitabine at RP2D compared to the standard of care gemcitabine and docetaxel in advanced Rb(+ve) leiomyosarcomas and dedifferentiated liposarcomas.
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity in phase 1. II. To determine cell cycle arrest and recovery with abemaciclib 200mg twice per day (BID) 5 to 7 days by blood thymidine kinase activity (Tka).
III. To assess the toxicity profile of the sequential abemaciclib followed by gemcitabine treatment using Common Terminology Criteria for Adverse Events (CTCAE) version 5 in phase 1 \& phase 2.
IV. To determine the preliminary objective response rate (ORR) by Response Criteria in Solid Tumors (RECIST)1.1 in phase 1.
V. To compare overall survival (OS) of sequential abemaciclib followed by gemcitabine at RP2D to the standard of care gemcitabine and docetaxel in phase 2.
VI. To compare the objective response rate (ORR) at time of best response by RECIST1.1 of sequential abemaciclib followed by gemcitabine at RP2D to the standard of care gemcitabine and docetaxel in phase 2.
VII. To compare PFS and ORR after cross-over in each treatment arm. VIII. To identify mechanisms of resistance to sequential treatment through correlative studies of the cell cycle genes.
OUTLINE: Patients in phase 1 part A are assigned to cohort 1 or 2. Patients in phase 2 are randomized to arm A or arm B and may cross over to the alternate arm after disease progression.
PHASE 1 PART A:
COHORT I: Patients receive abemaciclib orally (PO) twice per day (BID) on days 1-5 and 15-19 of each cycle and gemcitabine intravenously (IV) over 90 minutes on days 8 and 22 of each cycle. Cycles repeat every 28 days for up to 2 years of total treatment in the absence of disease progression or unacceptable toxicity. Patients may change to Phase 1 Part B treatment once the recommended schedule is determined. Patients also undergo computed tomography (CT) during screening and on study. Additionally, patients undergo blood sample collection during screening and on study.
COHORT II: Patients receive abemaciclib PO BID on days 1-7 and gemcitabine IV over 90 minutes on day 10 of each cycle. Cycles repeat every 21 days for up to 2 years of total treatment in the absence of disease progression or unacceptable toxicity. Patients may change to Phase 1 Part B treatment once the recommended schedule is determined. Patients also undergo CT during screening and on study. Additionally, patients undergo blood sample collection during screening and on study.
PHASE 1 PART B: Patients receive the selected treatment schedule, Cohort 1 or Cohort 2, as above. Cycles repeat every 21 or 28 days for up to 2 years of total treatment in the absence of disease progression or unacceptable toxicity.
PHASE 2:
ARM A: Patients receive abemaciclib PO BID and gemcitabine IV on the schedule determined in phase 1 of the trial. Cycles repeat every 21 or 28 days for up to 2 years of total treatment in the absence of disease progression or unacceptable toxicity. At the time of disease progression, patients may cross over to arm B. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy during screening and optionally on study.
ARM B: Patients receive gemcitabine IV over 90 minutes on days 1 and 8 of each cycle and docetaxel IV over 60 minutes on day 8 of each cycle. Cycles repeat every 21 days for up to 2 years of total treatment in the absence of disease progression or unacceptable toxicity. At the time of disease progression, patients may cross over to arm A. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy during screening and optionally on study.
After completion of study treatment, patients are followed up every 3 months for up to 2 years.
