Phase II Study on the Efficacy of Pemigatinib in Recurrent or Metastatic Solid Tumors with FGFR1, FGFR2, or FGFR3 Alterations

Trial ID: 2024-512729-10-00
Protocol: UC-GMP-2305
Sponsor: Unicancer

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Objectives

The primary objective of this study is to evaluate the **efficacy** of pemigatinib monotherapy on tumor growth kinetics and tumoral response in patients with recurrent and/or metastatic cancer harboring a FGFR alteration, such as fusion/rearrangement or activating mutation. This is clinically relevant as it aims to determine the potential of pemigatinib in managing cancers with specific genetic alterations, which could lead to more targeted and effective treatment options for patients with limited therapeutic alternatives.

Secondary objectives include assessing various efficacy endpoints and other clinical outcomes:

Overall response rate (ORR)
Clinical benefit rate (CBR)
Duration of response (DoR)
Progression-free survival
Time to treatment failure
Overall survival
Safety and tolerability of pemigatinib
Quality of life
Exploratory objective: Relevance of efficacy monitoring using longitudinal ctDNA sampling

These secondary objectives are crucial for providing a comprehensive understanding of the treatment's impact on patient outcomes, including survival rates, quality of life, and potential adverse effects, thereby informing clinical decision-making and future research directions.

Participants

The clinical trial involves participants diagnosed with **recurrent or metastatic solid cancer** harboring a FGFR1, 2, or 3 fusion/rearrangement or activating mutation, outside of the approved indications for any selective FGFR inhibitor in France. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. Participants are required to have adequate hematologic, hepatic, and renal function, as well as measurable disease according to RECIST1.1 criteria. The trial population was selected based on the absence of appropriate therapeutic alternatives and the potential benefit from FGFR inhibitor treatment, as assessed by the physician. Lifestyle considerations include the requirement for adequate contraception use by both men and women of childbearing potential during the trial and for a specified period after the last dose of pemigatinib. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **pemigatinib** monotherapy in patients with recurrent or metastatic solid tumors harboring FGFR alterations. This is a Phase II, randomized, double-blind, controlled trial. The trial is expected to commence recruitment on November 1, 2024, and conclude by May 31, 2028. Participants will be involved in the study for a maximum treatment period of six months, with the possibility of early termination if specific conditions arise, such as disease progression, unacceptable toxicity, or withdrawal of consent.

The trial will include several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically or cytologically confirmed solid tumors, adequate hematologic, hepatic, and renal function, and measurable disease according to RECIST1.1. Following the screening, participants will undergo regular follow-up visits to monitor tumor growth kinetics and tumoral response, as well as to assess safety and tolerability. The primary endpoint is the proportion of patients experiencing an objective response or a significant decrease in tumor growth kinetics. Secondary endpoints include overall response rate, clinical benefit rate, duration of response, progression-free survival, time to treatment failure, overall survival, and quality of life assessments.

The end-of-study visit will occur after the completion of the treatment period or upon early termination. Participants will be evaluated for any adverse events and overall treatment outcomes. The trial will ensure that all participants provide informed consent and adhere to the study protocol, with the option to withdraw at any time. The study aims to provide valuable insights into the potential benefits of **pemigatinib** for patients with specific genetic alterations in their tumors.

Treatment

The clinical trial involves the administration of **Pemazyre** 4.5 mg tablets, which contain the active substance **pemigatinib**. Pemigatinib is a chemical compound classified as an oral protein kinase inhibitor, specifically targeting FGFR alterations. The pharmaceutical form of the medication is a tablet, and it is administered orally. The maximum daily dose is 13.5 mg, with a total maximum dose of 1701 mg over the course of the treatment. The treatment period is limited to a maximum of 6 months. Pemazyre is not formulated for pediatric use and is designated as an orphan drug. The product is manufactured by Incyte Biosciences Distribution B.V. and is authorized for use in the European Union under the marketing authorization number EU/1/21/1535/001.

In this trial, Pemazyre is used as a monotherapy to evaluate its efficacy in patients with recurrent and/or metastatic solid tumors harboring FGFR alterations, such as fusion/rearrangement or activating mutations. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen. The trial aims to assess the impact of pemigatinib on tumor growth kinetics and tumoral response in the specified patient population.

Efficacy

The efficacy of pemigatinib in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of patients experiencing an objective response or at least a 30% decrease in tumor growth kinetics at progressive disease (PD) on study treatment, compared to the tumor growth kinetics calculated from two pre-treatment evaluations. Tumor kinetics variation will be measured by the tumor growth ratio (TGr), defined as the ratio of the slope of tumor growth on treatment (between the nadir and PD) and the slope of tumor growth before treatment. The sum of diameters of target lesions will be calculated on each patient's imaging by blinded independent central review (BICR).

Secondary endpoints include the overall response rate (ORR), defined as the proportion of patients with a complete response (CR) or partial response (PR) as the best overall response during the study, based on RECIST1.1, as assessed by the BICR and by the physician. The clinical benefit rate (CBR) is defined as the proportion of patients with CR, PR, or stable disease (SD) lasting at least 24 weeks. Duration of response (DoR) will be measured from the time of first documented response until disease progression or death. Progression-free survival (PFS) will be measured from the date of inclusion to the date of first documented disease progression or death. Time to treatment failure (TTF) is defined as the time from inclusion to permanent study treatment discontinuation. Overall survival (OS) will be measured from the date of inclusion to the date of death from any cause. Safety and tolerability will be assessed by the occurrence of treatment-emergent adverse events (TEAEs) and treatment-related adverse events according to NCI CTCAE v5.0. Quality of life (QoL) will be evaluated using the EORTC QLQ-C30 at pre-treatment, 3- and 6-months post-treatment initiation, and at the end of treatment (EOT). Exploratory endpoints include the longitudinal assessment of FGFR alterations on circulating tumor DNA (ctDNA).

Inclusion and Exclusion Criteria

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Inclusion Criteria

Histologically or cytologically confirmed solid tumor
Patient with locally reccurent unresectable and/or advanced or metastatic disease harbouring a FGFR1,2,3 fusion/rearrangement or mutation (appendix 8 of the protocol)
Age ≥ 18 years
Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
Patient for whom there is no appropriate therapeutic alternative and for whom a FGFR inhibitor is indicated by the institution or the regional multidisciplinary consultation meeting and may derive a benefit, according to the physician assessment,
Estimated life expectancy >3 months
Mesurable disease according to RECIST1.1, whatever the disease location. Tumor lesions located in a previously irradiated area, or in an area subjected to other locoregional therapy, are considered measureable if progression has been clearly demonstrated in the lesion.
Availability of 2 pre-treatment tumor evaluations performed with an interval of at least 4 weeks and no more than 3 months between the examinations (CT or MRI, but same technics for both) and without any cancer treatment during this period
Patient with a minimal trend at 0.1 mm/day increase in tumor growth kinetics between pre-treatment and baseline scan, as assessed by the investigator
Adequate hematologic function: ANC > 1.5 x 109 /L; platelets > 75 x 109 /L; haemoglobin > 9.0 g/dL. Transfusion is allowed with a 2-week washout period before treatment initiation
Adequate hepatic function: ALT and AST < 2,5 x ULN (≤ 5 x ULN for liver metastasis); total bilirubin < 1.5 x ULN (< 2.5 x ULN if Gilbert’s syndrome or liver metastasis); ALP < 3 x ULN
Adequate renal function: serum creatinine clearance > 30 mL/minute based on Cockroft-Gault formula
Value of serum phosphate ≤ ULN and value of serum calcium within institutional normal range (or serum albumin-corrected calcium within normal range when serum albumin is outside of the normal range)
Potassium levels within institutional normal range; supplementation can be used to correct potassium level during the screening.
Men, and women of childbearing potential (WOCBP) must agree to use adequate contraception for the duration of trial participation and for at least one week after the last dose of pemigatinib. Men must also agree to not donate sperm and women must agree to not donate oocytes during the specified period
Women of childbearing potential must have a negative serum pregnancy test performed within 14 days before treatment initiation
Patient is affiliated to a social security system
Patient must have signed a written informed consent form prior to any trial specific procedures. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in signing the patient’s consent.

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Exclusion Criteria

Hematologic malignancies
History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful. A screening QTcF interval > 480 ms is excluded.
Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as elevated transaminases or cirrhosis); chronic HBV/HCV infection with no cirrhosis and no elevated transaminases is allowed
Known hypersensitivity or severe reaction to pemigatinib or excipients of pemigatinib (refer to the Investigator Brochure)
Patient with a disease and a FGFR alteration covered by a marketed indication for any selective FGFR inhibitor (e.g cholangiocarcinoma with FGFR2-fusion or a FGFR mutation are not eligible, while FGFR1 or 3 fusion are eligible)
Patient who received prior selective FGFR inhibitor
Patient who can be included in a recruiting study assessing FGFR inhibitor (including pemigatinib)
Prior anticancer therapy, including radiotherapy, endocrine therapy, immunotherapy, chemotherapy or other investigational agents within the last 4 weeks (6 weeks for nitrosoureas and mitomycin C). A 1-week washout is permitted for palliative radiation to non-CNS disease. Patients must have recovered (≤ Grade 1) from AEs from previously administered therapies or local treatments before treatment initiation (excluding alopecia, anemia and decreased creatinine clearance)
Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 14 days or five half-lives (whichever is shorter) before the first dose of study drug
Any condition which in the Investigator’s opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol
Inability or unlikeliness of the participant to comply with the dose schedule or with the medical evaluations and follow-up required by the trial because of geographic, familial, social, or psychological reasons
Current evidence of clinically significant corneal or retinal disorder as confirmed by ophthalmologic examination
Other current malignancy, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for 5 years or more and are deemed at negligible risk for recurrence, are eligible for the trial
History of calcium and phosphate hemostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues (exception: commonly observed calcifications in soft tissues such as skin, kidney tendon, or vessels due to injury, disease, or aging in the absence of systemic mineral imbalance)
Significant gastrointestinal disorder(s) that could interfere with absorption, metabolism, or excretion of pemigatinib
Known HIV infection except if undetectable viral load
Other active chronic or current infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment within 2 weeks before enrollment (participants with asymptomatic chronic infections on prophylactic treatment are allowed)
Inability to swallow and retain oral medication
Clinically significant or uncontrolled cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug/treatment administration, New York Heart Association Class III or IV congestive heart failure, and uncontrolled arrhythmia (participants with pacemaker or with atrial fibrillation and well-controlled heart rate are allowed)
Women who are pregnant or breastfeeding
History of hypovitaminosis D requiring supraphysiologic doses (eg, 50,000 UI/weekly) to replenish the deficiency.
Participation in another therapeutic trial within the 30 days prior to inclusion
Individuals deprived of liberty or placed under protective custody or guardianship