Overview
It's propose this pilot phase 2 study to explore the combination therapy of futibatinib with pembrolizumab in patients with metastatic microsatellite stable (MSS) endometrial carcinoma to provide a well-tolerated regimen for durable responses.
Description
Primary Objectives
- To evaluate the objective response rate (ORR) of futibatinib and pembrolizumab in patients with metastatic microsatellite stable (MSS) endometrial carcinoma.
- To evaluate the safety and tolerability.
Primary Endpoints
- Complete responses (CRs) and partial responses (PRs) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
- Adverse events (AEs: clinical manifestations and laboratory tests) and serious adverse events (SAEs) according to the NCI Common Terminology Criteria for Adverse Events [CTCAE] version 5.0.
Eligibility
Inclusion Criteria:
To be eligible for this trial, patients must meet all of the following eligibility
criteria.
- Patients with histologically confirmed locally advanced or metastatic endometrial
carcinoma that is not amenable to curative surgical- or radiation-based intervention,
who have received or declined at least one-line systemic chemotherapy.
- Known microsatellite stable (MSS) as pre-identified in a Clinical Laboratory
Improvement Amendments (CLIA)-certified laboratory
- At least one measurable disease as defined by Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1.
- Age ≥18 years.
- Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test
prior to administration of the first dose of futibatinib within 7 days prior to
initiation of therapy (C1D1), and must agree to use effective birth control initiated
immediately following negative serum pregnancy test during screening period, during
the study, and for at least 180 days after the last dose (or longer based on local
requirements). Female patients are not considered to be of child-bearing potential if
they are post-menopausal (no menses for 12 months without an alternative medical
cause) or permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral
oophorectomy).
Adequate organ functions as defined below:
Absolute neutrophil count (ANC) ≥ 1,000 /μL. Hemoglobin (Hb) ≥ 9 g/dL. Platelets ≥ 75,000
/μL. Total bilirubin ≤ 1.5 x ULN (upper limit of normal); or total bilirubin < 3 x ULN with
direct bilirubin ≤ ULN in patients with well documented Gilbert's Syndrome.
ALT ≤ 3 x ULN or ≤ 5 x ULN if liver metastases persist. Serum phosphate ≤ 1.5 x ULN. Serum
calcium ≤ ULN. Serum albumin ≥ 3 g/dL. Serum creatinine ≤ 1.5 x ULN or calculated
creatinine clearance (CrCl) ≥ 40 mL/min by the Cockcroft-Gault method* or 24-hour urine
collection.
*CrCl = (140-age) x (weight [kg]) x 0.85 / (72 x serum creatinine mg/dL)
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
- No prior treatment with anti-PD-(L)1 therapy and/or a FGFR inhibitor.
- Ability to read and fully understand the requirements of the trial, willingness to
comply with all trial visits and assessments, and willingness and ability to sign an
institutional review board (IRB)-approved written informed consent document.
- Any prior radiation must have been completed at least 14 days prior to the start of
study drugs, and patients must have recovered from any acute adverse effects prior to
the start of study treatment (Radiotherapy for extended field within 4 weeks or
limited field radiotherapy within 2 weeks).
- Ability to take oral medications without medical history of malabsorption or other
chronic gastrointestinal disease, or other conditions that may hamper compliance
and/or absorption of the study agents (feeding tube is not permitted).
- Provision of an archival tissue block, or 10 formalin-fixed paraffin-embedded (FFPE)
slides obtained within 6 months prior to study entry; or agreeing to have biopsies if
archival tissues are not available.
Exclusion Criteria:
- Patients who meet any of the following criteria will be not eligible for the study:
- Uncontrolled intercurrent illness including but not limited to ongoing or active
infection requiring intravenous antibiotics, symptomatic congestive heart failure (New
York Heart Association Class III or IV), history of myocardial infarction, unstable
angina, stroke or transient ischemic attack within 6 months before study enrollment,
history or current evidence of uncontrolled ventricular arrhythmia. Congenital long QT
syndrome, or any known history of torsade de pointes, or family history of unexplained
sudden death. Chronic diarrhea diseases considered to be clinically significant in the
opinion of the Investigator. Other severe acute or chronic medical or psychiatric
condition or laboratory abnormality that may increase the risk associated with study
participation or futibatinib and pembrolizumab administration, or may interfere with
the interpretation of study results, and in the judgment of the Investigator would
make the patient inappropriate for entry into this study.
- History and/or current evidence of any of the following disorders: Non-tumor related
alteration of the calcium-phosphorus homeostasis that is considered clinically
significant in the opinion of the Investigator; Ectopic mineralization/calcification,
including but not limited to soft tissue, kidneys, intestine, or myocardia and lung,
considered clinically significant in the opinion of the Investigator; and Retinal or
corneal disorder confirmed by retinal/corneal examination and considered clinically
significant in the opinion of the Investigator and a trained ophthalmologist who
performs the test.
- Having not recovered from a major surgical procedure or significant traumatic injury
(i.e., still needing additional surgical or medical care for these issues): major
surgical procedures ≤ 28 days of treatment entry, or minor surgical procedures ≤ 7
days. No waiting period required following port-a-cath or other central venous access
placement.
- Unresolved clinically significant Grade 2 toxicity from prior therapy.
- Patient has an inability to swallow oral medications. Note: Patient may not have a
percutaneous endoscopic gastrostomy (PEG) tube or be receiving total parenteral
nutrition (TPN).
- Clinically active bleeding, or active gastric or duodenal ulcer.
- Fridericia's corrected QT interval (QTcF =QT/∛(60/HR) ) > 470 ms on ECG conducted
during Screening. Patients with an atrioventricular pacemaker or other condition (for
example, right bundle branch block) that renders the QT measurement invalid are an
exception and the criterion does not apply.
- History of allergic reactions to the study drugs, or any component of the products.
- Currently receiving an investigational drug in a clinical trial or participating in
any other type of medical research judged not to be scientifically or medically
compatible with this study. If a patient is currently enrolled in a clinical trial
involving non-approved use of a device, then agreement with the investigator and the
sponsor is required to establish eligibility.
- Any treatment specifically for systemic tumor control given within 3 weeks before the
initiation of the study drugs, within 2 weeks if cytotoxic agents were given weekly,
within 6 weeks for nitrosoureas or mitomycin C, within 5 half-lives for targeted
agents with half-lives and pharmacodynamic effects lasting < 5 days, or failure to
recover from toxic effects of any therapy before the initiation of the study drugs. A
drug that has not received regulatory approval for any indication within 14 or 21 days
of treatment for a non-myelosuppressive or myelosuppressive agent, respectively.
- Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: Bacille
Calmette-Guérin vaccine, measles, mumps, rabies, rubella, typhoid vaccine,
varicella/zoster, and yellow fever. Seasonal influenza vaccines for injection are
generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines are live attenuated vaccines and are not allowed.
- Received strong inhibitors and inducers and sensitive substrates of CYP3A4 within 2
weeks (see appendix A).
- Symptomatic primary tumors or metastasis in the brain and/or central nervous system
that are uncontrolled with antiepileptics and require steroids at a dose of prednisone
> 10 mg/day or equivalent.
- Evidence of leptomeningeal or lymphangitic carcinomatosis.
- A history of another primary malignancy that is currently clinically significant,
requiring active intervention except for hormone therapy.
- Concurrent immunosuppressive therapy or steroid (> 10 mg/day prednisone or
equivalent).
- Previously documented or suspected autoimmune disease requiring active
immunosuppressive therapy (adequately treated skin rash or replacement therapy for
endocrinopathies is not excluded), and history of or current pneumonitis.
- Lactation or pregnancy.
- Known human immunodeficiency virus requiring HAART treatment due to unknown drug-drug
interactions or known active hepatitis B or C virus infection.