Adaptive Pembrolizumab and Axitinib for the Treatment of Advanced Clear Cell Renal Cell Carcinoma
This phase II trial studies how well adaptive treatment with pembrolizumab and axitinib works in treating patients with clear cell renal cell carcinoma (ccRCC) that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Typically, patients with advanced ccRCC are treated continuously regardless of whether tumor size is decreasing. During adaptive treatment, patients are closely monitored to see when the tumor size decreases. Once this happens, the combined drugs are stopped, and patients are closely monitored to see if the tumor size increases again, at which point the drugs are restarted. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Axitinib is in a class of medications called tyrosine kinase inhibitors. It interferes with cell communication and growth and may prevent tumor growth. Giving adaptive treatment with pembrolizumab and axitinib may be effective in treating advanced ccRCC.
Inclusion Criteria
- Unresectable advanced or metastatic renal cell carcinoma (RCC) to include only predominant clear cell histology
- Age ≥ 18 years or older at time of signing informed consent
- Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 within 28 days prior to registration
- Availability of formalin-fixed, paraffin-embedded (FFPE) archival tumor specimens, when available, and willingness of the subject to undergo fresh tumor biopsy prior to treatment initiation if archival tissue not available * If a target lesion is biopsied at screening, this lesion must be followed as non-target lesion after the biopsy unless it is the patient’s only target lesion * If there is only one target lesion, it should be followed as a target lesion regardless
- Have had no prior systemic therapy (treatment naïve) for mccRCC. Prior neoadjuvant or adjuvant therapy received for localized ccRCC is not allowed
- Measurable disease as defined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 within 28 days prior to registration
- Platelet count ≥ 100,000/μL (obtained within 28 days prior to first study treatment)
- Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L– without a red blood cell transfusion within 2 weeks of the screening test (obtained within 28 days prior to first study treatment)
- Absolute neutrophil count (ANC) ≥ 1,500/μL (obtained within 28 days prior to first study treatment)
- Creatinine clearance based on Cockcroft-Gault formula (glomerular filtration rate [GFR]) calculation: GFR ≥ 40 mL/min for subjects (obtained within 28 days prior to first study treatment)
- Serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≤ 2.5 upper limit of normal (ULN) (obtained within 28 days prior to first study treatment)
- Total bilirubin ≤ 1.5 upper limit of normal (ULN). Except in subjects with Gilbert’s syndrome (obtained within 28 days prior to first study treatment)
- Females of childbearing potential must have a negative serum pregnancy test within 28 days prior to registration. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
- Females of childbearing potential and males must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 150 days after treatment discontinuation for females and 210 days after treatment discontinuation for males. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method
- As determined by the enrolling physician or protocol designee, must have ability to comprehend and the willingness to sign written informed consent, and comply with study procedures for entire length of study to be eligible for study participation
- Patients with well-controlled hepatitis B, hepatitis C, or HIV will be considered eligible
Exclusion Criteria
- Has had major surgery within 4 weeks and/or has received radiation therapy within 2 weeks prior to cycle 1 day 1 (C1D1)
- Has received prior systemic anti-cancer therapy for RCC (e.g., vascular endothelial growth factor [VEGF]/vascular endothelial growth factor receptor [VEGFR], chemotherapy or mammalian target of rapamycin [mTOR]-targeting agents). Note: Prior neoadjuvant/adjuvant therapy for ccRCC is acceptable if last dose was received more than 3 months from start of C1D1
- Has a history of severe hypersensitivity reaction (e.g., generalized rash/erythema hypotension, bronchospasm, angioedema, or anaphylaxis) to axitinib or pembrolizumab
- Has a diagnosis of immunodeficiency OR is receiving a systemic steroid therapy exceeding physiologic corticosteroid dose or any other form of immunosuppressive therapy within 7 days prior to C1D1 * Note: Subjects with vitiligo, Sjögren’s syndrome, Type 1 diabetes, or resolved childhood asthma/atopy will not be excluded from the study. Subjects requiring intermittent use of bronchodilators, inhaled steroids, or local steroid injections will not be excluded from the study. Subjects with hypothyroidism, or adrenal or pituitary insufficiency who are stable on hormone replacement will not be excluded from the study
- Has a known additional malignancy that has progressed or has required active treatment in the last 1 year. Note: Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ such as breast cancer in situ are acceptable if they have undergone potentially curative therapy
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to C1D1
- Has a history of (non-infectious) pneumonitis that required steroids in the past 6 months or current pneumonitis
- Has an active infection requiring systemic therapy
- Has a known history of human immunodeficiency virus (HIV) infection (e.g. HIV 1 and/or 2 antibodies), that is not well controlled
- Has a known history of hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected), that is not well controlled
- Has a clinically significant gastrointestinal (GI) abnormality including: Malabsorption, total gastric resection, or any other condition that might affect the absorption of orally taken medication. Active GI bleeding, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy. Intraluminal metastatic lesion with suspected bleeding, inflammatory bowel disease, ulcerative colitis or other GI condition associated with increased risk of perforation
- 12-lead electrocardiogram (ECG) will be performed during screening. If the initial QT interval corrected by Fridericia's correction formula (QTcF) is found to be > 500 msec, two additional EKGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is ≤ 500 msec, the subject meets eligibility in this regard
- Has a known history of any of the following cardiovascular conditions within 6 months of C1D1 of therapy: * Myocardial infarction * Unstable angina pectoris * Cardiac angioplasty or stenting * Coronary/peripheral artery bypass graft * Class III or IV congestive heart failure per New York Heart Association * Cerebrovascular accident or transient ischemic attack
- Has poorly controlled hypertension defined as systolic blood pressure (SBP) ≥ 160 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg. Subjects with initial screening blood pressure (BP) ≥ 160/90 mmHg can be treated with anti-hypertensive medication to achieve a well-controlled status and are eligible with reassessed SBP/DBP of < 150/95 mm Hg
- Has evidence of inadequate wound healing or active bleeding
Additional locations may be listed on ClinicalTrials.gov for NCT06860386.
Locations matching your search criteria
United States
Florida
Tampa
PRIMARY OBJECTIVES:
I. Assess the acceptability of enrollment on an adaptive therapy approach.
II. Assess the median 12 months progression-free survival (PFS) rate of patients on adaptive therapy.
III. To assess the feasibility, acceptability and preliminary efficacy of a response-based multi-drug adaptive therapy approach with pembrolizumab-axitinib (pembro-axi) in patients with metastatic clear cell renal cell carcinoma (mccRCC).
IV. To evaluate patient reported outcomes, health care utilization, and healthcare costs of a response-based multi-drug adaptive therapy approach with pembro-axi in patients with mccRCC.
SECONDARY OBJECTIVES:
I. Assess the improvement of patient reported outcomes (PROs) of patients on adaptive therapy.
II. Assess the median progression-free survival (PFS) time of patients on adaptive therapy.
III. Assess the median overall survival (OS) time of patients on adaptive therapy.
IV. Assess the proportion of subjects with persistent disease control not requiring disease reinitiation for more than 12 months after therapy discontinuation.
V. Assess safety and toxicity.
VI. Assess intra-tumoral changes in radiomic properties as indicators of evolution, response, and resistance to treatment via traditional and novel radiomically defined habitats.
OUTLINE:
PEMBRO-AXI: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 of each cycle and axitinib orally (PO) twice daily (BID) on days 1-21 of each cycle. Cycles repeat every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. After completion of cycle 3, patients undergo disease response assessment with computed tomography (CT) or magnetic resonance imaging (MRI). Patients whose tumor has decreased in size by > 20% move to the observation phase. Patients whose tumor has not decreased in size by > 20% continue to receive pembro-axi every 21 days for up to 48 months in the absence of disease progression or unacceptable toxicity. Patients continue to undergo disease response assessment with CT or MRI every 9 weeks and move to the observation phase once tumor size has decreased by > 20%.
OBSERVATION PHASE: Patients undergo blood sample collection every 3 weeks and CT or MRI every 9 weeks. Patients whose tumor increases to its original size or more resume pembro-axi therapy as described above.
Patients undergo blood sample collection, and CT or MRI throughout the study and may optionally undergo biopsy on study. Patients may also undergo biopsy during screening.
After completion of study treatment, patients are followed up at 30 days and then every 6 months until death or 2 years after end of therapy visit, whichever comes first.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMoffitt Cancer Center
Principal InvestigatorJonathan Alexander Chatzkel
- Primary IDMCC-23473
- Secondary IDsNCI-2025-01856
- ClinicalTrials.gov IDNCT06860386