Trial Title:
Testing the Addition of an Anti-cancer Drug, Abemaciclib, to the Usual Chemotherapy Treatment (Gemcitabine) for Soft Tissue Sarcoma
NCT ID:
NCT06498648
Condition:
Advanced Soft Tissue Sarcoma
Dedifferentiated Liposarcoma
Leiomyosarcoma
Metastatic Soft Tissue Sarcoma
Stage III Soft Tissue Sarcoma of the Trunk and Extremities AJCC v8
Stage IV Soft Tissue Sarcoma of the Trunk and Extremities AJCC v8
Conditions: Official terms:
Sarcoma
Leiomyosarcoma
Liposarcoma
Alovudine
Gemcitabine
Docetaxel
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Crossover Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Abemaciclib
Description:
Given PO
Arm group label:
Phase 2 Arm A (abemaciclib, gemcitabine)
Arm group label:
Phase I Part A Cohort I (abemaciclib, gemcitabine)
Arm group label:
Phase I Part A Cohort II (abemaciclib, gemcitabine)
Arm group label:
Phase I Part B (abemaciclib, gemcitabine)
Other name:
LY 2835219
Other name:
LY-2835219
Other name:
LY2835219
Other name:
Verzenio
Intervention type:
Procedure
Intervention name:
Biopsy
Description:
Undergo tumor biopsy
Arm group label:
Phase 2 Arm A (abemaciclib, gemcitabine)
Arm group label:
Phase 2 Arm B (gemcitabine, docetaxel)
Arm group label:
Phase I Part A Cohort I (abemaciclib, gemcitabine)
Arm group label:
Phase I Part A Cohort II (abemaciclib, gemcitabine)
Arm group label:
Phase I Part B (abemaciclib, gemcitabine)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Phase 2 Arm A (abemaciclib, gemcitabine)
Arm group label:
Phase 2 Arm B (gemcitabine, docetaxel)
Arm group label:
Phase I Part A Cohort I (abemaciclib, gemcitabine)
Arm group label:
Phase I Part A Cohort II (abemaciclib, gemcitabine)
Arm group label:
Phase I Part B (abemaciclib, gemcitabine)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Drug
Intervention name:
Docetaxel
Description:
Given IV
Arm group label:
Phase 2 Arm B (gemcitabine, docetaxel)
Other name:
Docecad
Other name:
RP 56976
Other name:
RP-56976
Other name:
RP56976
Other name:
Taxotere
Other name:
Taxotere Injection Concentrate
Intervention type:
Other
Intervention name:
Fluorothymidine F-18
Description:
Given IV
Arm group label:
Phase I Part A Cohort I (abemaciclib, gemcitabine)
Arm group label:
Phase I Part A Cohort II (abemaciclib, gemcitabine)
Arm group label:
Phase I Part B (abemaciclib, gemcitabine)
Other name:
18F-FLT
Other name:
3'-Deoxy-3'-(18F) Fluorothymidine
Other name:
3'-deoxy-3'-[18F]fluorothymidine
Other name:
ALOVUDINE F-18
Other name:
Fluorothymidine F 18
Intervention type:
Drug
Intervention name:
Gemcitabine
Description:
Given IV
Arm group label:
Phase 2 Arm A (abemaciclib, gemcitabine)
Arm group label:
Phase 2 Arm B (gemcitabine, docetaxel)
Arm group label:
Phase I Part A Cohort I (abemaciclib, gemcitabine)
Arm group label:
Phase I Part A Cohort II (abemaciclib, gemcitabine)
Arm group label:
Phase I Part B (abemaciclib, gemcitabine)
Other name:
dFdC
Other name:
dFdCyd
Other name:
Difluorodeoxycytidine
Intervention type:
Procedure
Intervention name:
Positron Emission Tomography
Description:
Undergo PET scan
Arm group label:
Phase I Part A Cohort I (abemaciclib, gemcitabine)
Arm group label:
Phase I Part A Cohort II (abemaciclib, gemcitabine)
Arm group label:
Phase I Part B (abemaciclib, gemcitabine)
Other name:
Medical Imaging, Positron Emission Tomography
Other name:
PET
Other name:
PET Scan
Other name:
Positron emission tomography (procedure)
Other name:
Positron Emission Tomography Scan
Other name:
Positron-Emission Tomography
Other name:
proton magnetic resonance spectroscopic imaging
Other name:
PT
Summary:
This phase 1/2 trial tests the side effects and best dose of abemaciclib when added to
gemcitabine and compares the effectiveness of that treatment to the usual treatment of
gemcitabine with docetaxel for the treatment of patients with soft tissue sarcoma that
may have spread from where it first started to nearby tissue, lymph nodes, or distant
parts of the body (advanced) or that has spread from where it first started (primary
site) to other places in the body (metastatic) (phase 1) or patients with leiomyosarcoma
or dedifferentiated liposarcoma (phase 2). Abemaciclib is in a class of medications
called kinase inhibitors. It works by blocking the action of an abnormal protein that
signals tumor cells to multiply. This helps slow or stop the spread of tumor cells.
Gemcitabine is a chemotherapy drug that blocks the cells from making DNA and may kill
tumor cells. Docetaxel is in a class of medications called taxanes. It stops cancer cells
from growing and dividing and may kill them. Giving abemaciclib with gemcitabine may be
safe and effective when compared to treatment with gemcitabine and docetaxel for patients
with advanced or metastatic soft tissue sarcoma or leiomyosarcoma or dedifferentiated
liposarcoma.
Detailed description:
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.
EXPLORATORY OBJECTIVE:
I. To determine cell cycle arrest and recovery with abemaciclib 200mg BID 5 to 7 days by
fluorothymidine F-18 (18F-FLT) positron emission tomography (PET) and its association
with blood Tka.
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
14-18 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 receive
18F-FLT IV and undergo PET/computed tomography (CT) during screening and on study.
Additionally, patients undergo blood sample collection during screening and on study, as
well as possible tumor biopsy during screening.
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 receive 18F-FLT IV and undergo PET/CT during screening and on study. Additionally,
patients undergo blood sample collection during screening and on study, as well as
possible tumor biopsy during screening.
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 may also undergo tumor biopsy during screening.
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 may also undergo tumor
biopsy during screening.
After completion of study treatment, patients are followed up every 3 months for up to 2
years.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Phase 1: Patients must have advanced/metastatic histologically confirmed soft tissue
sarcoma (STS) and have received at least one prior standard systemic therapy (prior
gemcitabine is allowed)
- Phase 2: Patients must have pathologically confirmed leiomyosarcoma or
dedifferentiated liposarcoma. Prior gemcitabine is not allowed
- Patients must have presence of measurable/assessable tumor
- Patients must have intact Rb gene expression in the baseline tumor biopsy or
archived tumor sample, as assessed by immunohistochemistry (at MD Anderson: clone
G3- 245, BD Pharmagen, RRID:AB_385259, Clinical Laboratory Improvement Act [CLIA]
certified antibody)
- Age ≥ 18 years. Because no dosing or adverse event data are currently available on
the use of abemaciclib in combination with gemcitabine in patients <18 years of age,
children are excluded from this study
- Eastern Cooperative oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
- Absolute neutrophil count ˃1.2K/µL
- Hemoglobin ˃ 9.0 g/dL
- Platelets ˃ 100K/mm^3
- Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2 unless data exists supporting
safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2
- Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN), patient with
Gilbert's syndrome ≤ 2.0 times ULN, or direct bilirubin within normal limits
- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) ≤
1.5 × institutional ULN
- Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 1.5 ×
institutional ULN
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression
- Patients with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of
the investigational regimen are eligible for this trial
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association (NYHA) Functional Classification. To
be eligible for this trial, patients should be class congestive heart failure (CHF)
II or better
- Patients must have a life expectancy of greater than 6 months
- Females of childbearing potential must have a negative serum pregnancy test within
one week of trial enrollment and be willing to use an adequate method of
contraception to avoid pregnancy throughout the trial and for up to 6 months after
the last dose of drug therapy. The effects of abemaciclib on the developing human
fetus are unknown. For this reason and because CDK 4/6 inhibiting agents as well as
gemcitabine are known to be teratogenic, women of child-bearing potential and men
must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry and for the duration of study
participation. Should a woman become pregnant or suspect she is pregnant while she
or her partner is participating in this study, she should inform her treating
physician immediately. Men treated or enrolled on this protocol must also agree to
use adequate contraception prior to the study, for the duration of study
participation, and 4 months after completion of abemaciclib administration
- Ability to understand and the willingness to sign a written informed consent
document. Legally authorized representatives may sign and give informed consent on
behalf of study participants
- Patient is capable of swallowing oral medications
Exclusion Criteria:
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the exception of alopecia
- Patients who are receiving any other investigational agents. There must be no
investigational drug use within 30 days or 5 half-lives of receiving the first dose
of treatment on this treatment
- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to abemaciclib or gemcitabine
- Patients with uncontrolled intercurrent illness or any other significant
condition(s) that would make participation in this protocol unreasonably hazardous
- Pregnant women are excluded from this study because abemaciclib is a CDK4/6
inhibiting agent with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with abemaciclib or gemcitabine, breastfeeding
should be discontinued if the mother is treated with abemaciclib or gemcitabine
- Use of strong CYP34A inhibitors which cannot be discontinued by the patient prior to
trial initiation. The washout period of these drugs should be 5 half-lives
- Progression on prior CDK4 inhibitor therapy
- Phase 2 only: Prior gemcitabine-based chemotherapy
- Presence of significant cardiac disease. Significant cardiac disease includes
personal history of any of the following conditions: syncope of cardiovascular
etiology, ventricular arrhythmia of pathological origin (including, but not limited
to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest
- Patients must not have received or be scheduled to receive radiation therapy within
7 days or less from gemcitabine administration
- Patients must not have had major surgery within 14 days prior to randomization
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
January 19, 2025
Completion date:
October 1, 2026
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Cancer Institute (NCI)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06498648
