Panitumumab, Regorafenib, or TAS-102, in Treating Patients With Metastatic and/or Unresectable RAS Wild-Type Colorectal Cancer

Stage IV Colorectal Cancer AJCC v8 Clinical Trial

Official title:

PULSE: A Randomized, Phase II Open Label Study of PanitUmumab RechaLlenge Versus Standard Therapy After Progression on Anti-EGFR Therapy in Patients With Metastatic and/or Unresectable RAS Wild-Type Colorectal Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03992456
• Other study ID #: ACCRU-GI-1623
• Secondary ID: NCI-2019-03306AC
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: April 24, 2020
• Est. completion date: October 7, 2024

Study information

• Verified date: April 2024
• Source: Academic and Community Cancer Research United
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies how well retreatment with panitumumab works compared to standard of care regorafenib or trifluridine and tipiracil hydrochloride (TAS-102) in treating patients with colorectal cancer that is negative for RAS wild-type colorectal cancer has spread to other places in the body (metastatic), and/or cannot be removed by surgery (unresectable), and is negative for resistance mutations in blood. Treatment with panitumumab may interfere with the ability of tumor cells to grow and spread. Some tumors need growth factors to keep growing. Growth factor antagonists, such as regorafenib, may interfere with the growth factor and stop the tumor from growing. Drugs used in chemotherapy, such as TAS-102, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving panitumumab may work better in treating patients with colorectal cancer than with the usual treatment of regorafenib or TAS-102.

Description:

PRIMARY OBJECTIVE:

I. To compare the overall survival (OS) in molecularly selected patients with metastatic colorectal cancer (CRC) receiving panitumumab rechallenge versus standard therapy (TAS-102 or regorafenib).

SECONDARY OBJECTIVES:

I. To compare the progression free survival (PFS) in molecularly selected patients with metastatic CRC receiving panitumumab rechallenge versus standard therapy (TAS-102 or regorafenib).

II. To define the objective response rate (ORR) in patients receiving panitumumab rechallenge versus standard therapy (TAS-102 or regorafenib).

III. To define the clinical benefit rate (CBR = complete response + partial response + stable disease >= 4 months) in patients receiving panitumumab rechallenge versus standard therapy (TAS-102 or regorafenib).

IV. To compare the safety and tolerability of panitumumab rechallenge versus standard therapy (TAS-102 or regorafenib).

V. To compare quality of life (QOL) between panitumumab rechallenge versus standard therapy (TAS-102 or regorafenib) as measured by the linear analogue self-assessment (LASA) questionnaires.

CORRELATIVE RESEARCH OBJECTIVES:

I. To assess plasma pharmacodynamics biomarkers of response and resistance to therapy.

II. To explore any correlation between tissue and blood based biomarkers and clinical outcomes.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive panitumumab intravenously (IV) over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days for a maximum of 24 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive trifluridine and tipiracil hydrochloride orally (PO) twice daily (BID) on days 1-5 and 8-12, or regorafenib PO once daily (QD) on days 1-21, at the discretion of the treating physician. Treatment repeats every 28 days for a maximum of 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 3 years after randomization.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 12
• Est. completion date: October 7, 2024
• Est. primary completion date: December 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Most recent Guardant360 blood collection date =< 90 days prior to randomization.

• NOTE: If a patient does not have Guardant360 test results available, enrollment in ACCRU_GI-1611 (COLOMATE) is strongly encouraged.

• Greater than 90 days has elapsed between the most recent treatment with an anti-epidermal growth factor receptor gene (EGFR) therapy (cetuximab or panitumumab) and blood collection for Guardant360 assay.

• Age >= 18 years.

• Histologically and/or cytologically confirmed adenocarcinoma of the colon or rectum that is metastatic and/ or unresectable.

• Documented wild-type in KRAS and NRAS (codons 12, 13, 59, 61, 117, and 146) and in BRAF codon 600, based on tumor tissue taken from primary or metastatic site prior to receipt of anti EGFR therapy.

• Progression, intolerance, or contraindication to:

• A fluoropyrimidine (e.g., 5-fluorouracil or capecitabine)

• Oxaliplatin

• Irinotecan

• An anti-vascular endothelial growth factor (VEGF) monoclonal antibody (including but not limited to bevacizumab, ramucirumab, or aflibercept).

• If the tumor has deficient mismatch repair proteins (dMMR) or is microsatellite instability (MSI)-high based on tumor tissue testing, an anti-programmed death (PD)-1 monoclonal antibody (including but not limited to nivolumab or pembrolizumab).

• Clinical or radiographic progression after treatment with an anti-EGFR monoclonal antibody (cetuximab and/or panitumumab) for at least 3 months (minimum of 6 biweekly treatments or 12 weekly treatments at full or partial dose).

• NOTE: Treatments do not need to be administered consecutively.

• NOTE: Dose reductions or delays are permitted.

• At least one site of disease that is measurable by Response Evaluation Criteria in Solid Tumors (RECIST) criteria that has not been previously irradiated; if the patient has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation.

• Life expectancy >= 3 months per estimation of investigator.

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1, or 2.

• Absolute neutrophil count (ANC) >= 1500/mm^3 without colony stimulating factor support (obtained =< 7 days prior to randomization).

• Platelet count >= 75,000 /mm^3 (obtained =< 7 days prior to randomization).

• Hemoglobin > 8.0 g/dL (obtained =< 7 days prior to randomization).

• Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 7 days prior to randomization).

• Aspartate transaminase (AST) =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer) (obtained =< 7 days prior to randomization).

• Alanine aminotransferase (ALT) =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer) (obtained =< 7 days prior to randomization).

• Calculated creatinine clearance must be > 30 ml/min using the Cockcroft-Gault formula or serum creatinine < 1.5 x ULN (obtained =< 7 days prior to randomization).

• Women of child bearing potential and male partners of women of child bearing potential must agree to use two medically accepted methods of contraception, one of them being a barrier method during the study and for 2 months after the last dose of study drug(s).

• Negative serum pregnancy test done =< 7 days prior to randomization, for women of childbearing potential only.

• NOTE: Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Postmenopause is defined as amenorrhea >= 12 consecutive months.

• NOTE: Women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, ovarian suppression or any other reversible treatment.

• Ability to complete questionnaire(s) by themselves or with assistance.

• Capable of understanding and complying with the protocol requirements and has signed the informed consent document.

• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study).

• Willing to provide tissue and blood samples for correlative research purposes.

• Willing to allow transfer of tissue and blood samples, clinical information, and outcome data collected from this trial for future research.

Exclusion Criteria:

• Radiation therapy, hormonal therapy, biologic therapy, experimental therapy, or chemotherapy for cancer < 21 days prior to randomization.

• Therapeutic anticoagulation with Vitamin-K antagonists (e.g., warfarin).

• Maximum mutant allele frequency (highest allele frequency reported for any gene mutation) (MAF) less than 0.5% by Guardant360 assay.

• Detection of at least one of the following gene mutation(s) or amplification(s) by Guardant360 assay.

• BRAFV600E mutation (mutant allele frequency (MAF) >= 0.5% or amplification.

• EGFR mutation (MAF >= 0.5%). Note: EGFR S492R, K467, and R451C mutations are not an exclusion.

• ERBB2 (HER2) amplification.

• KRAS mutation (MAF >= 0.5%) or amplification.

• MET amplification.

• NRAS mutation (MAF >= 0.5%) or amplification.

• Prior treatment with both TAS-102 and regorafenib (prior treatment with either TAS-102 or regorafenib is permitted).

• Unable to swallow oral tablets (crushing of study treatment tablets is not allowed).

• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens. Note: This includes impaired heart function or clinically significant heart disease.

• Not recovered to baseline or Common Terminology for Adverse Events (CTCAE) version (v)5.0 =< grade 1 from toxicity due to all prior therapies except alopecia, oxaliplatin-related neuropathy, asymptomatic electrolyte abnormalities, and other non-clinically significant adverse events.

• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:

• Pregnant women.

• Nursing women.

• Men or women of childbearing potential who are unwilling to employ adequate contraception.

• Patients with known central nervous system (CNS) metastases. Note: Patients with radiated or resected lesions are permitted, provided the lesions are fully treated and inactive (based on repeat imaging >= 30 days after completion of definitive treatment), patients are asymptomatic, and no steroids to control symptoms related to CNS metastases have been administered for at least 30 days.

• Major surgical procedure, open biopsy, or significant traumatic injury =< 28 days prior to randomization (=< 56 days for hepatectomy, open thoracotomy, major neurosurgery) or anticipation of need for major surgical procedure during the course of the study.

• Serious, non-healing wound, ulcer, or bone fracture.

• History of stroke (cerebrovascular accident), transient ischemic attack (TIA), myocardial infarction (MI), unstable angina, cardiac or other vascular stenting, angioplasty, or cardiac surgery =< 6 months prior to randomization.

• History of cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers, calcium channel blockers, or digoxin =< 6 months prior to randomization.

• Known history of congestive heart failure - New York Heart Association (NYHA) >= class II.

• Known history of human immunodeficiency virus (HIV) seropositivity, acute or chronic active hepatitis B or C infection, or other serious chronic infection requiring ongoing treatment.

• History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest computed tomography (CT) scan.

• Subjects with any previously untreated or concurrent cancer that is distinct in primary site or histology from colorectal cancer except cervical cancer in-situ, treated basal cell carcinoma, or superficial bladder tumor. Note: Subjects surviving a cancer that was curatively treated and without evidence of disease or biochemical relapse (undetectable PSA for prostate cancer) for 3 or more years before randomization are allowed. All cancer treatments must be completed at least 3 years prior to randomization.

• Uncontrolled hypertension (systolic pressure > 150 mm HG or diastolic pressure > 90 mm Hg [National Cancer Institute (NCI)-CTCAE v5.0]) on repeated measurement despite optimal medical management.

• Evidence or history of bleeding diathesis or coagulopathy.

• Any hemorrhage or bleeding event >= NCI CTCAE v5.0 grade 3, =< 4 weeks prior to randomization.

• Ongoing active infection > grade 2 NCI-CTCAE v5.0.

• Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or excipients of the formulation given during the course of this trial.

• EXCEPTION: Cetuximab

• Any known history of malabsorption condition.

• Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results.

• Use of any herbal remedy (e.g. St. John's wort) =< 7 days prior to randomization.

• Use of strong CYP3A4 inducers or inhibitors =< 7 days prior to randomization.

Related Conditions & MeSH terms

• Adenocarcinoma
• Carcinoma
• Colonic Neoplasms
• Colorectal Neoplasms
• Metastatic Colon Adenocarcinoma
• Metastatic Colorectal Carcinoma
• Metastatic Rectal Adenocarcinoma
• Rectal Neoplasms
• Stage III Colon Cancer AJCC v8
• Stage III Colorectal Cancer AJCC v8
• Stage III Rectal Cancer AJCC v8
• Stage IIIA Colon Cancer AJCC v8
• Stage IIIA Colorectal Cancer AJCC v8
• Stage IIIA Rectal Cancer AJCC v8
• Stage IIIB Colon Cancer AJCC v8
• Stage IIIB Colorectal Cancer AJCC v8
• Stage IIIB Rectal Cancer AJCC v8
• Stage IIIC Colon Cancer AJCC v8
• Stage IIIC Colorectal Cancer AJCC v8
• Stage IIIC Rectal Cancer AJCC v8
• Stage IV Colon Cancer AJCC v8
• Stage IV Colorectal Cancer AJCC v8
• Stage IV Rectal Cancer AJCC v8
• Stage IVA Colon Cancer AJCC v8
• Stage IVA Colorectal Cancer AJCC v8
• Stage IVA Rectal Cancer AJCC v8
• Stage IVB Colon Cancer AJCC v8
• Stage IVB Colorectal Cancer AJCC v8
• Stage IVB Rectal Cancer AJCC v8
• Stage IVC Colon Cancer AJCC v8
• Stage IVC Colorectal Cancer AJCC v8
• Stage IVC Rectal Cancer AJCC v8
• Unresectable Colon Adenocarcinoma
• Unresectable Colorectal Carcinoma
• Unresectable Rectal Adenocarcinoma

Intervention

Biological:
• Panitumumab
Given IV

Other:
• Quality-of-Life Assessment
Ancillary studies
• Questionnaire Administration
Ancillary studies

Drug:
• Regorafenib
Given PO
• Trifluridine and Tipiracil Hydrochloride
Given PO

Locations

Country	Name	City	State
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Duke University Medical Center	Durham	North Carolina
United States	M D Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Mayo Clinic in Arizona	Scottsdale	Arizona
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	MedStar Washington Hospital Center	Washington	District of Columbia
United States	Aurora Cancer Care-Milwaukee West	Wauwatosa	Wisconsin

Sponsors (2)

Lead Sponsor	Collaborator
Academic and Community Cancer Research United	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Cell Free Tumor Deoxyribonucleic Acid (cfDNA)	A report will be generated for each clinical specimen, which may include (but not limited to) the presence or absence of relevant gene mutations or amplifications, along with the allele frequency. Mutations of interest include KRAS and NRAS exons 2, 3, and 4, BRAF, PIK3CA, EGFR, AKT, PTEN, MAP2K1, and MET. Amplifications of interest include MET, EGFR, KRAS, and ERBB2. Genes and alterations analyzed will be based on best available science at the time of analysis.	Baseline, at restaging, and at disease progression
Other	Circulating Protein Studies	Plasma samples will be analyzed for multiple soluble protein analytes, which may include (but not limited to) HGF, c-MET, EGF, HBEGF, TGF-alpha, EGFR, HER2, and CD73.	Up to 3 years
Other	Tumor Tissue Studies	Comprehensive mutational analysis will be performed on archived formalin fixed paraffin embedded (FFPE) tumor samples. This analysis may include, but is not limited to Next Generation Sequencing (NGS) and IHC where appropriate.	Up to 3 years
Primary	Overall Survival (OS)	OS is defined as the Time from randomization to death from any cause. The distribution of overall survival will be estimated using the method of Kaplan-Meier. Overall survival will be compared between the 2 treatment arms using the un-stratified log-rank test will be used.	2 years
Secondary	Progression Free Survival (PFS)	PFS is defined as the time from randomization to documentation of disease progression or death due to any cause, whichever is first. If the patient did not have any disease evaluation post randomization, PFS will be censored at one day after randomization. The distribution of progression free survival will be estimated using the method of Kaplan-Meier. Progression free survival will be compared between the 2 treatment arms using the log-rank test which is used for the primary endpoint analysis.	1 year
Secondary	Overall Response Rate (ORR)	Defined as the number of patients with a complete response (CR) or partial response (PR) (as defined by the Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) divided by the number of evaluable patients in each arm. ORR will be compared between the 2 treatment arms. Confidence intervals for the true success proportion will be calculated according to the approach of Clopper and Pearson.	2 years
Secondary	Clinical Benefit Rate	Defined as the number of patients with a complete response (CR), partial response (PR), or stable disease for >= 4 months (as defined by the RECIST 1.1) divided by the number of evaluable patients in each arm. Confidence intervals for the true success proportion will be calculated according to the approach of Clopper and Pearson.	4 months
Secondary	Incidence of Adverse Events	The maximum grade for each type of adverse event will be recorded for each patient in each cycle. The number of patients experiencing grade 3 or higher adverse events will be compared using Chi-Square or Fisher's Exact tests.	2 years
Secondary	Patient-reported Quality of Life	Patients reported quality of life (QOL) outcomes will be collected using the Linear Analog Self-Assessment (LASA) Questionnaire. Data will be collected each cycle. Mean values of the first question (regarding overall QOL) at each cycle will be plotted, and stratified by arm. Additional analyses using data collected from the LASA questionnaire may be performed. Score from 0-10, 0 is worse and 10 is better.	2 years