Rapid Sequencing of Approved Therapies in Patients with Metastatic or Unresectable Clear Cell Renal Cell Carcinoma

Introduction

• Org Study ID: GCO 21-1913
• NTC ID: NCT05188118
• Lead Sponsor Name: Icahn School of Medicine at Mount Sinai
• Status: RECRUITING

Conditions

• Clear Cell Renal Cell Carcinoma

Brief Summary

This is a pilot, single-center, single-arm study where 20 patients with metastatic or unresectable clear cell renal cell carcinoma will receive same sequential treatment strategy (Cabozantinib for 12 weeks, then proceed with Ipilimumab plus Nivolumab immunotherapy x4 over 12 weeks, then subsequent therapies depending on treatment response for another 12 weeks [Nivolumab for CR/PR/SD, Cabozantinib or Lenvatinib/Everolimus for PROG]).

Eligibility Criteria

Inclusion Criteria:

* Age ≥ 18 years at the time of study entry
* Capable of understanding and complying with the protocol requirements and must have signed the informed consent document
* ECOG performance status of 0 or 1 or KPS of at least 80%
* Life expectancy ≥ 12 weeks
* Histologically confirmed advanced (not amenable to curative surgery or radiation therapy) or metastatic (stage IV) RCC with predominantly clear cell component (sarcomatoid differentiation 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.
* Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation.
* Lesions invading or encasing any major blood vessels.
* Other clinically significant disorders that would preclude safe study participation.

1. Serious non-healing wound/ulcer/bone fracture.
2. Uncompensated/symptomatic hypothyroidism.
3. Moderate to severe hepatic impairment (Child-Pugh B or C).
* 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.
* Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per 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.
* Current or prior use of immunosuppressive medication within 21 days before the first dose of protocol therapy, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
* Pregnant or lactating females.
* Inability to swallow tablets.
* History of hypersensitivity to cabozantinib, nivolumab, ipilimumab, lenvatinib, everolimus, or any excipient or history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
* 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.
* History of leptomeningeal carcinomatosis.
* Treatment with systemic immune-stimulatory agents (including but not limited to IL-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment.
* Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving protocol therapy or anticipation that such a live, attenuated vaccine will be required during the study.
* Any prior Grade ≥3 irAE while receiving any previous immunotherapy agent, or any unresolved irAE > Grade 1.
* Active or prior documented autoimmune disease within the past 2 years including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone may be eligible for this study.
* Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) or history of GI disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug.
* History of primary immunodeficiency.
* History of prior allogeneic stem cell or solid organ transplant.
* Participation in another clinical study with an investigational product within 28 days prior to enrolment in the study.
* Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.