A Phase II Trial Evaluating the Efficacy of Cabozantinib With Patients With Refractory GCTs

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Brief Title

A Phase II Trial of Cabozantinib With Patients With Refractory GCTs

Official Title

A Phase II Trial Evaluating the Efficacy of Cabozantinib in the Treatment of Incurable Patients With Refractory Germ Cell Tumors

Brief Summary

      The purpose of the CTO-IUSCCC-0752 study is to investigate the use of Cabozantinib for
      patients with incurable, refractory germ cell tumors. Patients will be treated until evidence
      of disease progression, non-compliance with study protocol, unacceptable major toxicity, at
      subject's own request for withdrawal, or if the study closes for any reason.
    


Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Clinical benefit rate

Secondary Outcome

 Objective response rate

Condition

Germ Cell Tumor

Intervention

Cabozantinib

Study Arms / Comparison Groups

 Cabozantinib
Description:  Patients will be treated with Cabozantinib 60mg orally daily continuously until disease progression, unacceptable toxicity, or trial closure.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

25

Start Date

May 28, 2021

Completion Date

December 2025

Primary Completion Date

December 2024

Eligibility Criteria

        Inclusion Criteria:

          1. Written informed consent and HIPAA authorization for release of personal health
             information.

          2. Capable of understanding and complying with the protocol requirements.

          3. Age ≥ 18 years at the time of consent.

          4. Histological or serological evidence of germ cell tumor, including seminoma,
             non-seminoma, and women with ovarian GCTs.

          5. Must have progressed after first-line cisplatin based combination chemotherapy AND
             demonstrated progression following at least one salvage regimen for advanced germ cell
             neoplasm and now considered incurable with standard therapies, including further
             chemotherapy or surgery.

        5.1. "Failure" of prior therapy is defined as: 5.1.1. A >25% increase in the products of
        the perpendicular diameters of measurable tumor masses during prior therapy which are not
        amenable to surgical resection.

        5.1.2. The presence of new tumors that are not amenable to surgical resection 5.1.3. An
        increase in AFP or beta-hcg (two separate determinations at least one week apart are
        required if rising tumor markers are the only evidence of failure).

        NOTE: Subjects with clinically growing teratoma (normal declining tumor markers and
        radiographic or clinical progression) should be considered for surgery.

        Subjects with relapsed primary mediastinal non-seminomatous germ cell tumor (PMNSGCT) are
        eligible 7. Subjects with late relapse (>2 years from previous chemotherapy) not amenable
        to resection are eligible if they have received first line platinum based chemotherapy and
        are deemed not amenable to surgical resection (no need for 1 salvage regimen in late
        relapse patients to be eligible).

        8. Recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to any prior
        treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.

        9. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 10. Adequate
        laboratory values obtained within 10 days prior to registration for protocol therapy and as
        defined below: 10.1. Hemoglobin ≥9g/dL 10.2. WBC ≥2500/μL 10.3. Absolute neutrophil count
        ≥1500/mm3 10.4. Platelet count ≥100,000/mm3 10.5. Total bilirubin ≤1.5 X ULN except
        patients with documented Gilbert's syndrome (≤3 X ULN) 10.6. Alanine aminotransferase
        (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤3 X ULN; for
        patients with hepatic metastases, ALT and AST ≤5 X ULN; ALP ≤5 X ULN with documented bone
        metastases.

        10.7. Total bilirubin ≤ 1.5x ULN (for subjects with Gilbert's disease ≤ 3x ULN).

        10.8. Serum albumin ≥ 2.8 g/dl 10.9. (PT)/INR or partial thromboplastin time (PTT) test <
        1.3x the laboratory ULN 10.10. Serum creatinine ≤ 2.0 x ULN or calculated creatinine
        clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault equation:

          1. Males: (140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)

          2. Females: [(140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85 10.11.
             Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-h urine
             protein ≤ 1 g 11. Female subjects of childbearing potential should have a negative
             urine or serum pregnancy test within 72 hours prior to receiving the first dose of
             study medication. If the urine test is positive or cannot be confirmed as negative, a
             serum pregnancy test will be required.

             12. Female subjects of childbearing potential should be willing to use 2 methods of
             birth control or be surgically sterile, or abstain from heterosexual activity for the
             course of the study through 120 days after the last dose of study medication. Subjects
             of childbearing potential are those who have not been surgically sterilized or have
             not been free from menses for > 1 year.

             13. Male subjects should agree to use an adequate method of contraception starting
             with the first dose of study therapy through 120 days after the last dose of study
             therapy.

             Exclusion Criteria:

             1. Prior treatment with Cabozantinib. Receipt of any type of small molecule kinase
             inhibitor (including investigational kinase inhibitor) within 2 weeks before first
             dose of study treatment.

             3. Subjects who have not received ≥1 salvage treatment regimens (except late relapse)
             or have further potentially curative treatment options.

             4. Known brain metastases or cranial epidural disease unless adequately treated and
             stable for at least 4 weeks prior to first dose of study treatment. Subjects must have
             complete wound healing from major surgery or minor surgery before first dose of study
             treatment. Eligible subjects must be neurologically asymptomatic at the time of first
             dose of study treatment.

             5. Radiation therapy for bone metastasis within 2 weeks, or any other radiation
             therapy within 4 weeks prior to first dose of study treatment.

             6. Expecting to father children within the projected duration of the trial, starting
             with the pre-screening or screening visit through 120 days after the last dose of
             trial treatment.

             7. Treatment with investigational agent, any type of cytotoxic, biologic or other
             systematic anticancer therapy within 28 days prior to registration for protocol
             therapy.

             8. Subjects with another active malignancy is not allowed except for adequately
             treated basal cell or squamous cell skin cancer, in situ cervical cancer, Gleason <
             Grade 7 prostate cancers, or other cancer for which the subject has not received
             therapy for ≥1 year.

             9. History of psychiatric illness or social situations that would limit compliance
             with study requirements.

             10. The subject has uncontrolled, significant intercurrent or recent illness
             including, but not limited to, the following conditions: 10.1 Cardiovascular
             disorders:

        a. Congestive heart failure New York Heart Association Class 3 or 4, unstable angina
        pectoris, serious cardiac arrhythmias.

        b. Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic
        or > 90 mm Hg diastolic despite optimal antihypertensive treatment.

        c. Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other
        ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism)
        within 6 months before first dose of study treatment.

        10.c.1. Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 months are
        allowed if stable, asymptomatic, and treated with a stable dose of permitted
        anticoagulation (see exclusion criterion #6) for at least 1 week before first dose of study
        treatment.

        10.2 Gastrointestinal (GI) disorders associated with a high risk of perforation or fistula
        formation:

          1. The subject has evidence of tumor invading the GI tract, active peptic ulcer disease,
             inflammatory bowel disease (e.g., Crohn's disease), diverticulitis, cholecystitis,
             symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the
             pancreatic duct or common bile duct, or gastric outlet obstruction

          2. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess
             within 6 months before first dose of study treatment.

          3. Note: Complete healing of an intra-abdominal abscess must be confirmed before first
             dose of study treatment.

             11. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon
             (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary
             hemorrhage) within 12 weeks before first dose of study treatment.

             12. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
             manifestation.

             13. Lesions invading or encasing any major blood vessels. 14. Other clinically
             significant disorders that would preclude safe study participation per the
             investigator's opinion.

        a. Serious non-healing wound/ulcer/bone fracture. b. Uncompensated/symptomatic
        hypothyroidism. c. Moderate to severe hepatic impairment (Child-Pugh B or C). 15. Major
        surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain metastasis)
        within 2 weeks before first dose of study treatment. Minor surgeries within 10 days before
        first dose of study treatment. Subjects must have complete wound healing from major surgery
        or minor surgery before first dose of study treatment. Subjects with clinically relevant
        ongoing complications from prior surgery are not eligible.

        16. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
        electrocardiogram (ECG) within 14 days before first dose of study treatment.

        Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional ECGs at
        intervals of approximately 3 min must be performed within 30 min after the initial ECG, and
        the average of these three consecutive results for QTcF will be used to determine
        eligibility.

        17. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin
        inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet
        inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:

        a. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable
        guidelines) and low-dose low molecular weight heparins (LMWH).

        b. Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors
        rivaroxaban, edoxaban, or apixaban in subjects who are on a stable dose of the
        anticoagulant for at least 1 week before first dose of study treatment without clinically
        significant hemorrhagic complications from the anticoagulation regimen or the tumor.

        18. Pregnant or lactating females. 19. Inability to swallow tablets. 20. Previously
        identified allergy or hypersensitivity to components of the study treatment formulations.
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

Nabil Adra, MD, 317-274-5830, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04876456

Organization ID

CTO-IUSCCC-0752


Responsible Party

Sponsor-Investigator

Study Sponsor

Nabil Adra

Collaborators

 Exelixis

Study Sponsor

Nabil Adra, MD, Principal Investigator, Indiana University


Verification Date

May 2021