Cabozantinib and Pamiparib for the Treatment of Advanced of Refractory Solid Tumors

  • STATUS
    Recruiting
  • End date
    Jun 3, 2024
  • participants needed
    44
  • sponsor
    M.D. Anderson Cancer Center
Updated on 11 August 2022

Summary

This phase I trial finds the best dose and side effects of cabozantinib and pamiparib in treating patients with solid tumors that have spread to other places in the body (advanced) or does not respond to treatment (refractory). Cabozantinib and pamiparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Description

PRIMARY OBJECTIVES:

I. To define the maximum tolerated dose (MTD) or maximum administered dose (MAD) and dose-limiting toxic effects (DLTs) of cabozantinib and pamiparib.

II. To define the safety profiles of cabozantinib and pamiparib.

SECONDARY OBJECTIVES:

I. To perform plasma pharmacokinetic analyses of cabozantinib and pamiparib interaction.

II. To evaluate patient reported outcomes (PRO). III. To evaluate pre-identified mutations in circulating free deoxyribonucleic acid (DNA) (cfDNA) by next generation sequencing (NGS).

IV. To estimate complete responses (CRs), partial responses (PRs), stable disease >= 6 months (SD >= 6months), progression free survival (PFS) and overall survival (OS).

V. To relate changes in phosphorylated AKT (pAKT), phosphorylated ERK2 (pERK2), phosphorylated c-MET (pc-MET), phosphorylated PARP1 (PARP1-pY907), phosphorylated histone H2A variant H2AX (gamma-H2AX) and RAD51 in tumor specimens with antitumor efficacy.

VI. To relate cancer-associated mutations at baseline with antitumor efficacy. VII. To explore potential biomarkers of acquired resistance by comparing molecular signatures at baseline with those at time of relapse in patients in whom SD >= 6 months/CR/PR or a mixed response are documented, by next-generation deep sequencing or more sophisticated techniques.

OUTLINE: This is a dose-escalation study.

Patients receive cabozantinib orally (PO) once daily (QD) and pamiparib PO twice daily (BID). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 6 months.

Details
Condition Advanced Malignant Solid Neoplasm, Refractory Malignant Solid Neoplasm
Treatment Cabozantinib, pamiparib
Clinical Study IdentifierNCT05038839
SponsorM.D. Anderson Cancer Center
Last Modified on11 August 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Patients must have histologically confirmed advanced solid tumors refractory to standard-of-care (SOC) therapy; or no SOC therapy; or declined SOC. During dose expansion, patients have to have one of the following genetic and pathologic features as defined in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory as well
A deleterious BRCA1 or BRCA2 mutation (germline or somatic)
A surrogate biomarker for HRD: deleterious mutation or deletion of MRE11, RAD50, NBS1, ATM, ATR, CHEK1, CHEK2, PALB2, ARID1A, Fanconi anemia genes, and PTEN, or loss of PTEN by IHC, amplification of EMSY, etc
Patients in the dose-escalation phase must have evaluable and/or measurable disease as
defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patients
in the dose expansion phase must have measurable disease per RECIST 1.1 and at
least one additional lesion that can be biopsied
Patients age >= 18 years
For women of child-bearing potential (women who have not been postmenopausal for at least one year or are not surgically sterile) and all men, agreement to use highly effective contraception (e.g., hormonal contraception, barrier device, or abstinence) prior to study entry for the duration of study participation and for 180 days after the last dose of the study agents. Nonsterile males must avoid sperm donation for the duration of the study and for at least 6 months after the last dose of the study agents
White blood cell count >= 2,500/uL, without granulocyte colony-stimulating factor support (within 14 days before first dose of study treatment)
Absolute neutrophil count (ANC) >= 1,500/uL, without granulocyte colony-stimulating factor support (within 14 days before first dose of study treatment)
Hemoglobin >= 9 g/dL (within 14 days before first dose of study treatment)
Platelets >= 100,000/uL, without transfusion (within 14 days before first dose of study treatment)
Total bilirubin =< 1.5 x upper limit of normal (ULN) (upper limit of normal), or total bilirubin < 3.0 x ULN with direct bilirubin =< ULN in patients with well documented Gilbert's syndrome (within 14 days before first dose of study treatment)
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (AKP) =< 3 x ULN. AKP =< 5 x ULN with documented bone metastases (within 14 days before first dose of study treatment)
Serum creatinine =< 1.5 x ULN or calculated creatinine clearance >= 45 mL/min by the Cockcroft-Gault method (within 14 days before first dose of study treatment)
Serum albumin >= 2.8 g/dL (within 14 days before first dose of study treatment)
Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol), or 24-h urine protein =< 1 g (within 14 days before first dose of study treatment)
Prothrombin time (PT)/institutional normalized ratio (INR) or partial thromboplastin time (PTT) test < 1.3 x the laboratory ULN if not on therapeutic anticoagulation (within 14 days before first dose of study treatment)
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
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
No palliative radiation therapy delivered to the sole target lesions immediately before or during the study
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
No prior treatment with simultaneous inhibition of PARP and VEGF with or without c-MET inhibition (patients may have prior therapy targeting only the c-MET, VEGF, or PARP pathway). However, prior treatment with cabozantinib is not allowed
Willing to provide an archival tissue block, or 10 formalin-fixed paraffin-embedded (FFPE) slides

Exclusion Criteria

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 4 weeks if cytotoxic agents were given once every 3 to 4 weeks, within 6 weeks for nitrosoureas or mitomycin C, within 5 half-lives for targeted agents with half-lives and pharmacodynamic effects lasting < 5 days (a minimum of 10 days is required), or failure to recover from toxic effects of any therapy before the initiation of the study drugs
Radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible
Major surgery (e.g., laparoscopic nephrectomy, gastrointestinal (GI) surgery, removal or biopsy of brain metastasis) within 4 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
Unresolved grade 1 or higher toxicity from prior therapy that is clinically significant
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)
The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions
Cardiovascular disorders
Congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias
Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment
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
Note: Subjects with a diagnosis of incidental, subsegmental pulmonary embolism (PE) or deep vein thrombosis (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
Gastrointestinal (GI) disorders including those associated with a high risk of
perforation or fistula formation
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
Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose of study treatment
Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose of study treatment
Other clinically significant disorders that would preclude safe study
participation
Serious non-healing wound/ulcer/bone fracture
Uncompensated/symptomatic hypothyroidism
Moderate to severe hepatic impairment (Child-Pugh B or C)
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
No other anticancer-therapy (chemotherapy, immunotherapy, hormonal anti-cancer therapy, radiotherapy [except for palliative local radiotherapy]), biological therapy or other novel agent is to be permitted while the patient is receiving study medication. Patients on LHRH analogue treatment for more than 6 months are allowed entry into the study and may continue at the discretion of the Investigator
Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to first dose of study treatment after major surgery (e.g., removal or biopsy of brain metastasis). Subjects must have complete wound healing from major surgery or minor surgery before first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment. Leptomeningeal or lymphangitic carcinomatosis is not allowed
Patient has had prescription or non-prescription drugs or other products known to be moderate to strong inhibitors or inducers of CYP3A which cannot be discontinued at least 5 half-lives if known, or 14 days if unknown prior to day 1 of dosing, and withheld throughout the study until 2 weeks after the last dose of study drug
Herbal preparations are not allowed throughout the study. These herbal medications include but are not limited to: St. John's wort, kava, ephedra (ma hung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng. Patients should stop using these herbal medications 5 half-lives if known or 14 days if unknown prior to first dose of study treatment
Any known hypersensitivity or contraindication to the components of the study drugs
Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per electrocardiogram (ECG) within 14 days before first dose of study treatment [QTcf = QT/(RR^0.33); RR interval = 60/heart rate], or congenital long QT syndrome
Note: If a single electrocardiography (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
Pregnant or breastfeeding women
Serious active infection at the time of study entry, or another serious underlying medical condition that would impair the ability of the patient to receive study treatment
Any other active malignancy at time of first dose of study treatment or diagnosis of another malignancy within 3 years prior to first dose of study treatment that requires active treatment, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast
Grade 2 or higher peripheral neuropathy
Human immunodeficiency virus requiring highly active antiretroviral therapy (HAART) treatment due to unknown drug-drug interactions or has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or C virus (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [quantitative] is detected) infection: patients who have had active hepatitis B virus [HBV] or HCV infections in the past but have evidence of viral clearance as shown by negative viral load, i.e., undetectable HBV DNA or HCV RNA, will be eligible
Lesions invading or encasing any major blood vessels. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation
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
Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH)
Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases 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
Vaccination with live vaccine within 4 weeks of treatment start
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