A Phase 1b Study of Sitagliptin in Combination With Pembrolizumab in Refractory or Relapsed Advanced Renal Cell Carcinoma and Melanoma
This study is testing whether adding the drug sitagliptin to the standard immunotherapy pembrolizumab is safe and may help people with advanced melanoma or advanced renal cell carcinoma (kidney cancer) whose cancer has stopped responding to prior PD-1 or PD-L1 immunotherapy. The study has two parts. In the first part, small groups of participants will receive different doses of sitagliptin along with a fixed dose of pembrolizumab. This helps researchers find the highest dose of sitagliptin that can be given safely. In the second part, more participants will receive the safest dose to see how well the drug combination works against their cancer.
• Histologically and/or cytologically confirmed unresectable metastatic renal cell carcinoma with clear cell component with no neuroendocrine differentiation component) or unresectable metastatic melanoma (excluding uveal or mucosal melanoma) that have progressed on treatment with an anti-PD-1/PD-L1 mAb administered either as a monotherapy, or in combination with other immune checkpoint inhibitors or other therapies. Progression on treatment with an anti-PD-1/PD-L1 mAb is defined by meeting all of the following criteria:
∙ Has received at least 2 doses of an approved anti-PD-1/PD-L1 mAb
‣ Has demonstrated disease progression after anti-PD-1/PD-L1 mAb as defined by RECIST v1.1. The initial evidence of disease progression (PD) is confirmed by a second assessment no less than 4 weeks from the date of the first documented PD
‣ Progressive disease has been documented within 12 weeks from last dose of anti-PD-1/PD-L1 mAb (refractory disease) or ≥12 weeks from last dose of anti-PD-1/PD-L1 mAb (late relapse)
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2
• Measurable disease meeting the following criteria:
∙ At least 1 lesion of ≥10mm in the longest diameter for a non-lymph node or ≥15mm in the short-axis diameter for a lymph node that is serially measurable according to RECIST v1.1 using computerized tomography/magnetic resonance imaging (CT/MRI)
‣ Lesions that have had external beam radiotherapy (EBRT) or loco-regional therapies such as radiofrequency (RF) ablation must show subsequent evidence of substantial size increase to be deemed a target lesion
• Aged 18 years and older
• The participant is capable of understanding and complying with the protocol requirements and has signed the informed consent document
• Participants must have recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy to \< Grade 1 CTCAE unless clinically insignificant and/or stable on supportive therapy.
• No active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with the use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Women of childbearing potential (WOCBP) - defined as females who have experienced menarche, have not undergone permanent surgical sterilization (i.e., hysterectomy, bilateral oophorectomy, or bilateral tubal ligation), and are not postmenopausal (no menses for ≥12 consecutive months without an alternative medical cause) - must meet all of the following criteria:
∙ 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 must be performed and must be negative prior to enrollment.
‣ Agree to use at least one highly effective method of contraception during the study and for a minimum of 4 months after the last dose of pembrolizumab.
• Acceptable highly effective methods include:
⁃ Combined (estrogen- and progestogen-containing) hormonal contraception (oral, intravaginal, or transdermal)
⁃ Progestogen-only hormonal contraception (oral, injectable, or implantable)
⁃ Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
⁃ Bilateral tubal occlusion
⁃ Vasectomized partner (if confirmed as the sole sexual partner)
⁃ Complete sexual abstinence (only if this is the participant's usual and preferred lifestyle)
• Male participants must:
‣ Use a condom with spermicide during the study and for at least 4 months after the last dose of pembrolizumab, and
⁃ Ensure that their female partners of childbearing potential use an additional highly effective method of contraception during this period.
⁃ Able to swallow pills
⁃ Adequate archival tissue sample ( 5-10 slides at 5µm) of at least one tumor lesion is mandatory. If archival tissue is not available, Participant must agree to a new biopsy sample.