Neoplasms

All Conditions

Digestive System Diseases

Carcinoma

Colorectal Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Anti-Infective Agents

All Drugs and Chemicals

Antineoplastic Agents

Piperazine

Mebendazole

Piperazine citrate

DMP 777

Trifluridine

Palbociclib

Protein Kinase Inhibitors

Enzyme Inhibitors

Antimetabolites

Antiviral Agents

Patients receive binimetinib PO BID on days 1-28 and palbociclib PO QD on days 1-21. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

Patients receive trifluridine and tipiracil hydrochloride PO BID on days 1-5 and 8-12. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients with disease progression may optionally crossover to Arm A.

Binimetinib

Trifluridine and Tipiracil Hydrochloride

Scott Kopetz

This phase II trial studies how well binimetinib and palbociclib work compared to TAS-102 in treating patients with KRAS and NRAS mutation positive colorectal cancer that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Binimetinib and palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as TAS-102, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving binimetinib and palbociclib may work better compared to TAS-102 alone in treating patients with colorectal cancer.

PRIMARY OBJECTIVE:

I. The primary objective is to compare the progression-free survival (PFS) between those randomized to palbociclib/binimetinib and those randomized to trifluridine and tipiracil hydrochloride (TAS-102) in patients with refractory KRAS- or NRAS-mutant metastatic colorectal cancer (CRC).

SECONDARY OBJECTIVES:

I. To compare the overall response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria between those randomized to palbociclib/binimetinib and those randomized to TAS-102 in patients with refractory KRAS- or NRAS-mutant metastatic CRC.

II. To compare the overall survival (OS) between those randomized to palbociclib/binimetinib and those randomized to TAS-102 in patients with refractory KRAS- or NRAS-mutant metastatic CRC.

III. To determine the safety and tolerability of the recommended phase II dose of palbociclib in combination with binimetinib in patients with refractory KRAS- or NRAS-mutant metastatic CRC.

CORRELATIVE RESEARCH OBJECTIVES:

I. To determine the tumor mutational profiles that characterize groups of patients that predict for response or resistance to combination of palbociclib/binimetinib.

II. To determine the correlation between circulating tumor deoxyribonucleic acid (DNA) and tumor response or resistance to therapy with palbociclib/binimetinib or TAS-102.

III. To determine the association between Consensus Molecular Subtype based on gene expression profiling and response or resistance to combination of palbociclib/binimetinib.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive binimetinib orally (PO) twice daily (BID) on days 1-28 and palbociclib PO once daily (QD) on days 1-21. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive trifluridine and tipiracil hydrochloride PO BID on days 1-5 and 8-12. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients with disease progression may optionally crossover to Arm A.

After completion of study treatment, patients are followed up within 30-37 days and then every 12 weeks for up to 24 months.

Binimetinib and Palbociclib or TAS-102 in Treating Patients With KRAS and NRAS Mutant Metastatic or Unresectable Colorectal Cancer

Combination of MEK Inhibitor Binimetinib and CDK4/6 Inhibitor Palbociclib in KRAS and NRAS Mutant Metastatic Colorectal Cancers

Disease progression will be determined based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and will be documented at each enrolling site with no central review planned. PFS will be compared between treatment arms using the stratified log rank test at one-sided level 0.05. Kaplan-Meier methodology will be used to estimate the median PFS for each treatment arm, and Kaplan-Meier curves will be produced.

Assessment of response data will be performed on the basis of definitions of responses according to RECIST version (v)1.1. Objective response is defined as a complete or partial response by RECIST v1.1. This will be reported as the number of patients experiencing an objective response.

Will use Kaplan-Meier methods to evaluate time to event endpoints, and will report median OS and its 95% confidence interval.

The number of patients experiencing a grade 3+ adverse event, regardless of attribution, will be reported.

National Cancer Institute (NCI)

Academic and Community Cancer Research United

Arm A (Binimetinib, Palbociclib)

Trifluridine and Tipiracil Hydrochloride: Given PO

Arm B (Trifluridine and Tipiracil Hydrochloride)

After completion of treatment with Trifluridine and Tipiracil Hydrochloride: Given PO, patients were given the option of being treated with Palbociclib: Given PO, crossing over from arm B to arm A.

Crossover

In the safety run-in, an initial cohort will receive palbociclib orally once daily on days 1-21 out of a 28 day cycle and binimetinib orally twice per day continuously at 30 mg BID daily. The starting dose of palbociclib will be 100 mg orally once daily on days 1-21 out of a 28 day cycle. If the starting dose is not well tolerated, with 2 or more subjects experiencing excessive toxicity as defined in Section 7.15, then the dose will be reduced to 75 mg orally once daily on days 1-21 out of a 28 day cycle dose, and further de-escalation will be studied if needed to determine a safe and tolerable dose in this population of colorectal cancer patients.

Safety Run-In Cohort

Patients receive binimetinib PO BID on days 1-28 and palbociclib PO QD on days 1-21. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.\>\> \>\> Binimetinib: Given PO\>\>

\>\> Palbociclib: Given PO

Patients receive trifluridine and tipiracil hydrochloride PO BID on days 1-5 and 8-12. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients with disease progression may optionally crossover to Arm A.\>\>

\>\> Trifluridine and Tipiracil Hydrochloride: Given PO

Total

Age, Continuous

Gender

Sex/Gender, Customized

Race (NIH/OMB)

United States

Region of Enrollment

ECOG performance status evaluates a patient's ability to perform every-day tasks; a higher score is associated with more impairment.\>\> 0 - Fully active, able to carry on all pre-disease performance without restriction\>\>

1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work

ECOG Performance Status

Scott Kopetz, M.D.

Patients receive binimetinib PO BID on days 1-28 and palbociclib PO QD on days 1-21. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.\> \>\>

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\>\> Binimetinib: Given PO\>

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\>\> Palbociclib: Given PO

Patients receive trifluridine and tipiracil hydrochloride PO BID on days 1-5 and 8-12. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients with disease progression may optionally crossover to Arm A.\>

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\>\> Trifluridine and Tipiracil Hydrochloride: Given PO

Progression Free Survival (PFS)

Overall Response Rate

Overall Survival (OS)

Number of Participants With Adverse Events

Patients receive binimetinib PO BID on days 1-28 and palbociclib PO QD on days 1-21. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

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\> Binimetinib: Given PO

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\> Palbociclib: Given PO

Patients receive trifluridine and tipiracil hydrochloride PO BID on days 1-5 and 8-12. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients with disease progression may optionally crossover to Arm A.

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\> Trifluridine and Tipiracil Hydrochloride: Given PO

Overall Study

Symptoms and General Pathology

Neoplasm Metastasis

Recurrence

Neoplastic Processes

Disease Attributes

Antibodies

Antibodies, Monoclonal

Pembrolizumab

Avelumab

Immunomodulating Agents

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

SNK01 (low dose) administered once a week for five weeks.

SNK01 (medium dose) administered once a week for five weeks.

SNK01 (high dose) administered once a week for five weeks.

SNK01 (high dose) administered in combination with avelumab once every two weeks (14-day cycle) for five cycles.

SNK01 (high dose) administered in combination with pembrolizumab once every three weeks (21-day cycle) for five cycles.

Patient-specific ex vivo expanded autologous natural killer cells

SNK01

Avelumab is a humanized monoclonal antibody immune checkpoint blockade immunotherapy that targets the programmed cell death-ligand 1 (PD-L1).

Pembrolizumab is a humanized monoclonal antibody immune checkpoint blockade immunotherapy that targets the programmed cell death receptor-1 (PD-1).

Paul Chang, MPH

The purpose of the study is to evaluate the safety and preliminary efficacy of SNK01 (autologous natural killer cell), as a single agent and in combination with avelumab or pembrolizumab, for the treatment of subjects with advanced and/or metastatic refractory cancer that has failed three or more prior lines of conventional standard of care therapy.

Safety of SNK01 in Subjects With Pathologically Confirmed Metastatic and/or Unresectable Cancer Refractory to Conventional Therapy

Phase 1, Open-Label, Safety Study of Escalating Doses of Ex Vivo Expanded, Autologous Natural Killer Cells in Patients With Pathologically Confirmed Cancer Refractory to Conventional Therapy

Assessed by the incidence and severity of dose limiting toxicity (DLT) and other adverse events graded according to the National Cancer Institute's Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 5.0, or the cytokine release syndrome revised grading system.

Objective response rate (ORR) is defined by the percentage of subjects who achieve a confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Binimetinib and Palbociclib or TAS-102 in Treating Patients With KRAS and NRAS Mutant Metastatic or Unresectable Colorectal Cancer	NCT03981614	Metastatic Colo... Stage IV Colore... Stage IVA Color... Stage IVB Color... Stage IVC Color... Unresectable Ca...	Binimetinib Palbociclib Trifluridine an...	18 Years -	Academic and Community Cancer Research United
Safety of SNK01 in Subjects With Pathologically Confirmed Metastatic and/or Unresectable Cancer Refractory to Conventional Therapy	NCT03941262	Refractory Canc... Metastatic Canc... Recurrent Cance... Unresectable Ca... Solid Tumor, Ad... Advanced Cancer Advanced Solid ...	SNK01 Avelumab Pembrolizumab	18 Years - 75 Years	NKGen Biotech, Inc.
Binimetinib and Palbociclib or TAS-102 in Treating Patients With KRAS and NRAS Mutant Metastatic or Unresectable Colorectal Cancer	NCT03981614	Metastatic Colo... Stage IV Colore... Stage IVA Color... Stage IVB Color... Stage IVC Color... Unresectable Ca...	Binimetinib Palbociclib Trifluridine an...	18 Years -	Academic and Community Cancer Research United

Spots Global Cancer Trial Database for unresectable carcinoma