Pemigatinib for the Treatment of Metastatic or Unresectable Colorectal Cancer Harboring FGFR Alterations

Study Overview
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Brief Summary
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This phase II trial studies how well pemigatinib works in treating patients with colorectal cancer with mutations (alterations) in a FGFR gene and that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Pemigatinib may stop the growth of tumor cells by blocking FGFR, which is needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVE: I. To assess overall response rate (ORR) of pemigatinib in patients with metastatic or unresectable colorectal cancer harboring activating FGFR alterations. SECONDARY OBJECTIVES: I. To assess the clinical benefit rate (complete response + partial response + stable disease) with pemigatinib. II. To assess progression free survival (PFS) and overall survival (OS) with pemigatinib. III. Assess changes in patient quality of life (QOL) as measured by the linear analogue self-assessment (LASA) questionnaire. IV. Assess the frequency and severity of adverse events. CORRELATIVE RESEARCH OBJECTIVES: I. To assess plasma pharmacodynamic biomarkers of response and resistance to therapy. II. To explore any correlation between tissue and blood based biomarkers and clinical outcomes. OUTLINE: Patients receive pemigatinib orally (PO) once daily (QD) on days 1-21. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 3 years after registration.

Official Title
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A Phase II, Multicenter, Single-Arm Study of Pemigatinib in Patients With Metastatic or Unresectable Colorectal Cancer Harboring FGFR Alterations

Conditions
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Stage IVA Colorectal Cancer AJCC v8, FGFR1 Gene Amplification, FGFR1 Gene Mutation, FGFR1 Gene Translocation, FGFR2 Gene Amplification, FGFR2 Gene Mutation, FGFR2 Gene Translocation, FGFR3 Gene Amplification, FGFR3 Gene Mutation, FGFR3 Gene Translocation, Metastatic Colorectal Carcinoma, Stage III Colorectal Cancer AJCC v8, Stage IIIA Colorectal Cancer AJCC v8, Stage IIIB Colorectal Cancer AJCC v8, Stage IIIC Colorectal Cancer AJCC v8, Stage IV Colorectal Cancer AJCC v8, Stage IVB Colorectal Cancer AJCC v8, Stage IVC Colorectal Cancer AJCC v8, Unresectable Colorectal Carcinoma

Intervention / Treatment
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* Drug: Pemigatinib
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Registered to Colorectal and Liquid Biopsy Molecularly Assigned Therapy (COLOMATE) Academic and Community Cancer Research United (ACCRU)-GI-1611 and: COLOMATE Companion Trial Recommendation Form indicates patient qualifies to be screened for a COLOMATE companion trial COLOMATE Companion Trial Recommendation Form date of completion is =< 30 days prior to registration Histologically or cytologically confirmed diagnosis of metastatic or unresectable colorectal cancer (mCRC), based on documentation from local or outside review of pathology according to each site?s established institutional procedure Documentation of an activating genomic alteration(s) in FGFR1-3 (gain of function mutations, translocations, and amplifications allowed) Provide informed written consent Patient must have received and progressed on, or be intolerant to, each of the following treatments for mCRC (or have contraindication to these treatments): Fluoropyrimidine Oxaliplatin Irinotecan Anti-VEGF (vascular endothelial growth factor) monoclonal antibody, if eligible for this therapy Anti-EGFR (epidermal growth factor receptor) monoclonal antibody, if eligible for this therapy Measurable disease Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2 Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 28 days prior to registration) Platelet count >= 100,000/mm^3 (obtained =< 28 days prior to registration) Hemoglobin >= 9.0 g/dL (obtained =< 28 days prior to registration) Total bilirubin =< 1.5x upper limit of normal (ULN), or =< 2.5x ULN if patient has Gilbert syndrome or disease involving the liver (obtained =< 28 days prior to registration) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5x ULN (or =< 5x ULN in presence of suspected liver metastases) (obtained =< 28 days prior to registration) Serum phosphate < institutional ULN (obtained =< 28 days prior to registration) Serum calcium within institutional normal range, or serum albumin-corrected calcium within institutional normal range (if serum albumin is outside of the institutional normal range) (obtained =< 28 days prior to registration) Potassium levels > institutional lower limit of normal (supplementation can be used to correct potassium level during screening) (obtained =< 28 days prior to registration) Serum creatinine =< 1.5x ULN, or calculated creatinine clearance > 30 mL/min using the Cockcroft-Gault formula or 24-hours urine collection analysis (obtained =< 28 days prior to registration) Corrected QT interval (QTc) by Fridericia?s method (QTcF) assessed by electrocardiogram (ECG) completed =< 28 days prior to registration, and resulted as: QTcF =< 450 msec in men, or QTcF =< 470 msec in women Negative serum pregnancy test completed =< 7 days prior to registration, for women of childbearing potential only 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: Prior treatment with pemigatinib Prior treatment with a selective FGFR inhibitor =< 180 days (6 months) prior to registration Known hypersensitivity or severe reaction to an FGFR inhibitor, or to the excipients of pemigatinib (i.e. microcrystalline cellulose, sodium starch glycolate, and magnesium stearate) Current evidence of clinically significant corneal or retinal disorder confirmed by ophthalmologic examination Treatment with other investigational study drug for any indication for any reason, or receipt of anticancer medications =< 14 days prior to registration Major surgery =< 28 days prior to registration External beam radiation therapy =< 28 days prior to registration, or palliative radiation for non-central nervous system (CNS) disease =< 14 days prior to registration Brain metastases, central nervous system (CNS) metastases, leptomeningeal disease, or spinal cord compression NOTE: Patients who are asymptomatic or previously treated and stable, without evidence of progression for >= 28 days prior to registration are eligible NOTE: Patients taking concomitant corticosteroids and/or anticonvulsants are allowed if patient is on a stable or decreasing dose of such treatment for >= 28 days prior to registration History or presence of significant cardiovascular disease or condition including: Uncontrolled angina pectoris (Canadian Cardiovascular Society grade II-IV despite medical therapy) Congestive heart failure (New York Heart Association class III or IV) Uncontrolled arrhythmia requiring therapy. Note: Patients with a pacemaker and well-controlled rhythm for >= 28 days prior to registration are not excluded Any of the following occurring =< 6 months prior to registration: myocardial infarction, angioplasty, cardiac stenting, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack Failure to adequately recover (i.e. to =< grade 1 [according to Common Terminology Criteria for Adverse Events (CTCAE) version (v.)5] or to pre-treatment baseline) from adverse events (AEs) deemed by the investigator as clinically significant and attributed to prior therapy. Exception: alopecia Current use of prohibited medication Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers =< 14 days or 5 half-lives (whichever is shorter) prior to registration. Note: topical ketoconazole will be allowed History of hypovitaminosis D requiring supraphysiologic doses to replenish the deficiency. Note: patients receiving vitamin D food supplements are allowed History and/or current evidence of ectopic mineralization/calcification, including but not limited to soft tissue, kidneys, intestine, myocardia, or lung; with the exception of calcified lymph nodes and asymptomatic arterial or cartilage/tendon calcification Unable or unwilling to swallow pemigatinib and keep a medication diary, or significant gastrointestinal disorder(s) that could interfere with absorption, metabolism or excretion of pemigatinib per the discretion of the investigator Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown: Pregnant women Nursing women Women of childbearing potential or men able to father children who have a female partner of childbearing potential, who are unwilling to employ acceptable contraception Known history of human immunodeficiency (HIV) infection or positivity on immunoassay confirmed per local standards Note: HIV test is not required for screening, but patients with a known history of HIV infection will be excluded Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection Other known active malignancy =< 5 years prior to registration EXCEPTIONS: Non-melanotic skin cancer or carcinoma in situ of the cervix, provided there is no known active disease and no additional therapy for the condition is ongoing or required during the trial period NOTE: anti-estrogen/androgen therapy or bisphosphonates allowed Co-morbid systemic illness, other severe concurrent disease, or psychiatric illness/social situation which, in the judgment of the investigator, would make the patient inappropriate for entry into this study, limit compliance with study requirements, or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimen

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (pemigatinib)<br>Patients receive pemigatinib PO QD on days 1-21. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity. | Drug: Pemigatinib<br>* Given PO<br>* Other names: INCB054828;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | Defined as the percentage of patients, among evaluable patients, who experience an objective response per RECIST 1.1. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach of Clopper and Pearson. | At 36 weeks after registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical benefit rate | Clinical Benefit Rate is defined as the number of patients that experience a complete or partial response within 36 weeks post registration, or have stable disease for at least 36 weeks post registration, divided by the number of evaluable patients. Analysis of this endpoint will mirror that of the primary objective. | Up to 36 weeks after registration | 
| Progression-free survival (PFS) | Progression-free survival (PFS) is defined as the time from study entry to the first of either disease progression or death from any cause, where disease progression is determined based on RECIST 1.1 criteria. PFS will be estimated using the Kaplan-Meier method. The median PFS and corresponding 95% confidence interval will be reported. Patients who do not experience disease progression or death while on protocol will be censored at the last disease assessment date. | From study entry to the first of either disease progression or death from any cause, assessed up to 3 years after registration | 
| Overall survival (OS) | Overall survival (OS) is defined as the time from study entry to death from any cause. Will be estimated using the Kaplan-Meier method. The median OS and corresponding 95% confidence interval will be reported. | From study entry to death from any cause, assessed up to 3 years after registration | 
| Quality of Life (QOL) as measured by the LASA [item 1: Overall QOL] | Quality of Life (QOL) was measured using item 1: Overall QOL of the Linear Analogue Self-Assessment (LASA) Questionnaire on a 0-10 scale, with 0=as bad as it can be and 10=as good as it can be. The QOL scores was converted to a 100-point scale, with 0=Low QOL and 100=Best QOL. Change from baseline to Week 36 will be calculated by subtracting the baseline scores from the scores at Week 36. Negative change indicates the QOL decrease and positive change indicates the QOL improvement. | From baseline up to 36 weeks | 
| Incidence of adverse events | Adverse events will be summarized by frequency and severity using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. | Up to 3 years after registration |