Pembrolizumab and Cabozantinib S-malate in Treating Patients with Locally Advanced, Recurrent, or Metastatic Kidney Cancer

Status: Active

Description

This phase I / II trial studies how well cabozantinib s-malate works when given together with pembrolizumab in treating patients with kidney cancer that has come back, spread from where it started to nearby tissue or lymph nodes, or spread to other places in the body. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and cabozantinib s-malate may work better in treating patients with renal cell carcinoma.

Eligibility Criteria

Inclusion Criteria

  • Subjects must have histological or cytological documentation of locally advanced, recurrent, or metastatic renal cell carcinoma
  • Be willing and able to provide written informed consent/assent for the trial
  • Stated willingness to comply with all study procedures and be available for the duration of the trial
  • Have measurable or evaluable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 from toxicities related to any prior treatments, unless adverse events (AE[s]) are clinically non-significant and/or stable on supportive therapy
  • Confirmed availability of representative archival tumor specimens in paraffin blocks (preferred) or >= 10 unstained slides, with an associated pathology report * Acceptable samples include core needle biopsies for deep tumor tissue or excisional, incisional, or punch biopsies for cutaneous, subcutaneous, or mucosal lesions * Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is therefore not acceptable * A subject with insufficient or unavailable archival tissue may be eligible, upon discussion with the principal investigator, if the subject is willing to consent to undergo a pretreatment core, punch, or excisional/incisional biopsy sample collection of the tumor
  • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  • Absolute neutrophil count (ANC) >= 1,500 /mcL, performed within 10 days of treatment initiation
  • Platelets >= 100,000/mcL, performed within 10 days of treatment initiation
  • Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment), performed within 10 days of treatment initiation
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN, performed within 10 days of treatment initiation
  • Urine protein =< 1+ or =< 30 mg/dL OR urine protein/creatinine ratio =< 1, performed within 10 days of treatment initiation
  • Serum total bilirubin =< 1.5 x ULN, performed within 10 days of treatment initiation OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN; for subjects with Gilbert’s disease =< 3 mg/dL
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases, performed within 10 days of treatment initiation
  • Albumin >= 2.5 mg/dL, performed within 10 days of treatment initiation
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants, performed within 10 days of treatment initiation
  • Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants, performed within 10 days of treatment initiation
  • Female subject of childbearing potential should have a negative urine or serum pregnancy 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
  • Female subjects of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study medication * Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
  • Male subjects of childbearing potential must 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 * Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

Exclusion Criteria

  • Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
  • Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy equivalent to >= 10 mg/day of prednisone, or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
  • Has a known history of active tuberculosis (TB) (Bacillus tuberculosis)
  • Has had prior treatment with pembrolizumab
  • Has had prior treatment with cabozantinib
  • Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
  • Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent * Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: subjects with =< grade 2 hypertension managed with medication are an exception to this criterion and may qualify for the study * Note: subjects with =< grade 2 endocrinopathy (e.g. hypothyroidism or adrenal insufficiency managed with medication) are an exception to this criterion and may qualify for the study
  • Has had major surgery within 4 weeks or minor surgery within 2 weeks prior to study day 1; subjects must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
  • Prior treatment with immune checkpoint inhibitors is allowed, provided that no treatment-related grade >= 3 adverse events (other than grade 3 endocrinopathy managed with replacement therapy) were observed and at least a minimum of 28 days have elapsed between the last dose of prior treatment and the proposed cycle 1 day 1
  • Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, carcinoma in situ or superficial bladder cancer, low-grade prostate cancer, intraductal papillary mucinous neoplasm (IPMN), and other low grade cancers that is suitable for active surveillance in the opinion of the investigator
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; active CNS metastases will be defined as brain lesions that 1) require intervention with surgery, stereotactic radiosurgery (SRS), or whole brain radiotherapy (WBRT) or 2) require anti-epileptic therapy, systemic steroid treatment, or intrathecal therapy; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks after completion of focal therapy brain metastases and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
  • Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed
  • Has history of solid organ transplantation
  • Has history of osteonecrosis of the jaw
  • Has history of reversible posterior leukoencephalopathy syndrome
  • Has history of wound dehiscence or complications requiring medical intervention within 6 months of study entry
  • Has history of (non-infectious) pneumonitis that required steroids or active, non-infectious pneumonitis
  • Has an active infection requiring systemic therapy with IV antibiotics
  • Has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: * Cardiovascular disorders: ** Symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmias ** Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment ** Stroke (including transient ischemic attack [TIA]), myocardial infarction, or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 3 months before randomization * Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: ** Tumors invading the GI-tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction ** Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 6 months before randomization; complete healing of an intra-abdominal abscess must be confirmed before study initiation * Has clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon within 3 months before randomization * Known endobronchial disease manifestation; patients with suspected endobronchial disease on imaging who have no evidence of endobronchial disease on bronchoscopy are allowed; patients with treated endobronchial disease are also allowed provided they are stable * Lesions invading major pulmonary blood vessels
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Is pregnant or breastfeeding, or expecting to conceive or 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
  • Has an inability to swallow tablets or capsules
  • Has a previously identified allergy or hypersensitivity to components of the study treatment formulations
  • Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
  • Has received a live vaccine within 30 days of planned start of study therapy * Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed

Locations & Contacts

Colorado

Aurora
University of Colorado Hospital
Status: Active
Contact: Elaine T. Lam
Phone: 720-848-0170
Colorado Springs
UCHealth Memorial Hospital Central
Status: Active
Contact: Geetika Srivastava
Phone: 719-365-6568
Fort Collins
Poudre Valley Hospital
Status: Active
Contact: Steven Robert Schuster
Email: Steven.Schuster@uchealth.org
Lone Tree
UCHealth Lone Tree Health Center
Status: Active
Contact: Elaine T. Lam
Phone: 720-848-0170

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the efficacy based on objective response rate (ORR = complete response [CR] + partial response [PR]) of pembrolizumab and cabozantinib s-malate (cabozantinib) when administered in combination in subjects with locally advanced or metastatic renal cell carcinoma.

SECONDARY OBJECTIVES:

I. To characterize dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) for the combination.

II. To assess other measures of anti-tumor activity of the combination of pembrolizumab and cabozantinib in subjects with locally advanced or metastatic renal cell carcinoma.

III. Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST) (immune-related response criteria) response.

IV. Progression-free survival.

V. Time to progression of overall disease.

VI Time to progression of bone metastasis or skeletal-related event.

VII. Clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD]).

VIII. Duration of response or disease stability.

IX. Duration on treatment in subjects treated beyond progression.

EXPLORATORY OBJECTIVES:

I. Bone turnover markers, such as beta C-terminal telopeptide (beta-CTX), bone specific alkaline phosphatase, and procollagen type 1 amino-terminal propeptide (P1NP).

II. Bone scan responses.

III. PD-L1 immunohistochemistry (IHC) testing on archival samples.

IV. PD-L1 IHC testing on fresh tumor baseline and/or post-treatment samples.

V. Evaluation of immuno-oncology markers.

OUTLINE: This is a phase I, dose-escalation study of cabozantinib s-malate followed by a phase II study.

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and cabozantinib s-malate orally (PO) once daily (QD) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30-90 days.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
University of Colorado Hospital

Principal Investigator
Elaine T. Lam

Trial IDs

Primary ID 16-2300
Secondary IDs NCI-2017-01777
Clinicaltrials.gov ID NCT03149822