Metastatic Renal Cell CarcinomaPhase 1/2NCT03149822
Study of Pembrolizumab and Cabozantinib in Patients With Metastatic Renal Cell Carcinoma
A Phase 1/2 study testing Cabozantinib and Pembrolizumab in people with Metastatic Renal Cell Carcinoma, run by University of Colorado, Denver at 5 sites in United States.
Trial summary
This is a phase I/II open-label study designed to evaluate the combination of pembrolizumab and cabozantinib in subjects with locally advanced, recurrent, or metastatic renal cell carcinoma. Read more about this study
- Who is it for?
- Ages 18 to 100 years
- Conditions the study is for
- Metastatic Renal Cell Carcinoma
- What is being tested?
- Cabozantinib and Pembrolizumab
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 45 participants
- Where
- 5 sitesUnited States
- Study dates
- 28 Sep 2017to 16 Feb 2024
- Phase
- Phase 1/2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Subjects must have histological or cytological documentation of renal cell carcinoma
- Subjects must have locally advanced, recurrent, or metastatic disease.
- Be willing and able to provide written informed consent/assent for the trial.
- Stated willingness to complywith all study procedures and be available for the duration of the trial.
- Be ≥ 18 years of age on day of signing informed consent.
- Have measurable or evaluable disease based on RECIST 1.1.
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- Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any prior treatments, unless 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 ECOG Performance Scale.
- Demonstrate adequate organ function as defined by desired lab values.
- 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 (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 - 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 (Section 5.7.1) must agree to use an adequate method of contraception as outlined in Section 5.7.1- 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.
Who cannot join
- 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 steroiderapy 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 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.
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- Note: Subjects with stable, treated hypothyroidism or adrenal insufficiency may qualify for the study
- 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.
- Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
- Subjects with hypertension managed with medication are an exception to this criterion and may qualify for the study.
- 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 for 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 BP > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment.
- Stroke (including 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., HBsAg reactive) or Hepatitis C (e.g., HCV 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.
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
United States5 sites
University of Colorado Denver
Aurora, Colorado, 80045
Memorial Hospital Central
Colorado Springs, Colorado, 80909
Poudre Valley Hospital
Fort Collins, Colorado, 80528
Highlands Ranch Hospital
Highlands Ranch, Colorado, 80129
UCHealth Lone Tree Medical Center
Lone Tree, Colorado, 80124
About this study
Official title: Phase I/II Study of Pembrolizumab and Cabozantinib in Patients With Metastatic Renal Cell Carcinoma
This is a phase I/II open-label study designed to evaluate the combination of pembrolizumab and cabozantinib in subjects with locally advanced, recurrent, or metastatic renal cell carcinoma. Sequential dose escalation of cabozantinib with standard dose pembrolizumab will occur in the phase I dose escalation part of the study to determine the recommended phase 2 dose (RP2D). Subsequently, subjects will receive cabozantinib at the RP2D in combination with pembrolizumab in the phase II dose expansion part of the study.
Read the detailed description
Primary Objectives
- To determine the efficacy based on objective response rate [ORR = complete response (CR) + partial response (PR)] of pembrolizumab and cabozantinib when administered in combination in subjects with locally advanced or metastatic renal cell carcinoma..
Secondary Objectives
- To characterize dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) for the combination.
- 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.
- Conditions
- Metastatic Renal Cell Carcinoma
- Being tested
- Cabozantinib, Pembrolizumab
- Medical subject headings
- Carcinoma, Renal Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CabozantinibDrug
Also called Cabometyx
Pharmaceutical form: tablets Route of administration: oral
PembrolizumabDrug
Also called MK-3475, Keytruda
Pharmaceutical form: solution Route of administration: injection
| Study group | Role | What they receive |
|---|---|---|
| Phase 1: Pembrolizumab 200 mg plus Cabozantinib 40mg | Experimental | Pembrolizumab 200 mg intravenous (IV) infusion on day 1 of each 21-day cycle in combination with cabozantinib 40 mg orally once daily until disease progression, unacceptable toxicity, or consent withdrawal. Receives: Drug: Cabozantinib; Drug: Pembrolizumab |
| Phase 1: Pembrolizumab 200 mg plus Cabozantinib 60mg | Experimental | Pembrolizumab 200 mg intravenous (IV) infusion on day 1 of each 21-day cycle in combination with cabozantinib 60 mg orally once daily until disease progression, unacceptable toxicity, or consent withdrawal. Receives: Drug: Cabozantinib; Drug: Pembrolizumab |
| Phase 2: Pembrolizumab 200 mg plus Cabozantinib at the RP2D | Experimental | Pembrolizumab 200 mg intravenous (IV) infusion on day 1 of each 21-day cycle in combination with cabozantinib at the RP2D orally once daily for up to 35 cycles, until disease progression, unacceptable toxicity, or consent withdrawal. All participants who stop pembrolizumab after 35 cycles with SD or better may be eligible for up to an additional 17 cycles (approximately 1 year) of pembrolizumab treatment if they progress after stopping pembrolizumab from the initial treatment phase. Receives: Drug: Cabozantinib; Drug: Pembrolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Efficacy of Pembrolizumab and Cabozantinib Based on Objective Response Rate
Measured through the complete response (CR) + partial response (PR)] of pembrolizumab and cabozantinib when administered in combination in subjects with locally advanced or metastatic renal cell carcinoma. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Measured: Beginning of study to end of study, up to 5 years
Secondary outcomes (6)
Maximally Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)
- The MTD is defined as the highest dose level with no more than 1 DLT reported in 6 DLT-evaluable subjects.
- The Recommended Phase 2 Dose (RP2D) of cabozantinib will be selected based on the clinical data and will not exceed the MTD. If < 2/6 subjects experience a DLT at 60 mg daily during dose escalation, then 60 mg daily will be considered the RP2D. If ≥ 2/6 subjects experience DLTs at 60 mg daily, and ≤ 1/6 subjects experience a DLT at 40 mg daily, then 40 mg daily will be considered the RP2D. The dose of pembrolizumab will be constant at 200 mg IV every 3 weeks.
Measured: Throughout Cycle 1, up to 21 days
Dose Limiting Toxicities
Assessed through Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. Dose Limiting Toxicity (DLT) was defined as any of the following events occurring during the DLT assessment window (21 days) and is assessed by the investigator to be likely related to study treatment (pembrolizumab and/or cabozantinib).
- Grade ≥ 3 non-hematologic, non-hepatic adverse events
- Grade 3 nausea, vomiting, or diarrhea lasting >72 hours despite maximal medical therapy.
- Grade ≥ 4 neutropenia (ANC < 500 cells/μL) lasting > 7 days
- Grade ≥ 3 febrile neutropenia
- Grade ≥ 4 anemia
- Grade ≥ 4 thrombocytopenia, or Grade 3 thrombocytopenia associated with clinically significant bleeding
- Grade ≥ 3 elevation of serum hepatic transaminase (ALT or AST).
- Grade ≥ 3 elevation of serum total bilirubin.
- ALT or AST > 3 × upper limit of normal (ULN) AND total bilirubin >2 × ULN will require permanent treatment discontinuation.
Measured: Throughout Cycle 1, up to 21 days
Progression-Free Survival
Measured as the time it takes for an occurrence of documented disease progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Measured: Beginning of study to end of study, or death, whichever comes first, up to 5 years
Overall Survival
Measured as the time it takes for an occurrence of death due to any cause
Measured: Beginning of study to end of study, or death, whichever comes first, up to 5 years
Disease Control Rate (DCR), AKA Clinical Benefit Rate (CBR)
DCR is the sum of the complete response, partial response, and stable disease rates
Measured: Beginning of study to end of study, or death, whichever comes first, up to 5 years
Duration of Response
Duration of time that patients maintain RECIST response to treatment
Measured: Time of first response as measured by RECIST 1.1 to time of progression or death, whichever comes first, up to 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 May 2017
- Study start28 Sep 2017
- Primary completion14 Dec 2022
- Study completion16 Feb 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (19)Papers the sponsor has linked to this study.
- Other trials for Metastatic Renal Cell CarcinomaStudies of the same condition, open and under way.
- More trials run by University of Colorado, DenverThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 45 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Colorado, Denver
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Sponsor
- Investigators
- Elaine Lam, MD, Principal investigator, University of Colorado, Denver
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03149822
- Sponsor's protocol ID
- 16-2300.cc
- Other IDs
- NCI-2017-01777
- Status last verified
- Mar 2025
- First submitted
- 28 Apr 2017
- Last updated
- 13 Mar 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Gunturi A, McDermott DF. Potential of new therapies like anti-PD1 in kidney cancer. Curr Treat Options Oncol. 2014 Mar;15(1):137-46. doi: 10.1007/s11864-013-0268-y.
PubMed 24504486Philips GK, Atkins MB. New agents and new targets for renal cell carcinoma. Am Soc Clin Oncol Educ Book. 2014:e222-7. doi: 10.14694/EdBook_AM.2014.34.e222.
PubMed 24857106Hato T, Zhu AX, Duda DG. Rationally combining anti-VEGF therapy with checkpoint inhibitors in hepatocellular carcinoma. Immunotherapy. 2016;8(3):299-313. doi: 10.2217/imt.15.126. Epub 2016 Feb 11.
PubMed 26865127Massari F, Santoni M, Ciccarese C, Santini D, Alfieri S, Martignoni G, Brunelli M, Piva F, Berardi R, Montironi R, Porta C, Cascinu S, Tortora G. PD-1 blockade therapy in renal cell carcinoma: current studies and future promises. Cancer Treat Rev. 2015 Feb;41(2):114-21. doi: 10.1016/j.ctrv.2014.12.013. Epub 2015 Jan 6.
PubMed 25586601Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13. doi: 10.1056/NEJMoa1510665. Epub 2015 Sep 25.
PubMed 26406148Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, Golshayan A, Rayman PA, Wood L, Garcia J, Dreicer R, Bukowski R, Finke JH. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res. 2009 Mar 15;15(6):2148-57. doi: 10.1158/1078-0432.CCR-08-1332. Epub 2009 Mar 10.
PubMed 19276286Tartour E, Pere H, Maillere B, Terme M, Merillon N, Taieb J, Sandoval F, Quintin-Colonna F, Lacerda K, Karadimou A, Badoual C, Tedgui A, Fridman WH, Oudard S. Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev. 2011 Mar;30(1):83-95. doi: 10.1007/s10555-011-9281-4.
PubMed 21249423Terme M, Colussi O, Marcheteau E, Tanchot C, Tartour E, Taieb J. Modulation of immunity by antiangiogenic molecules in cancer. Clin Dev Immunol. 2012;2012:492920. doi: 10.1155/2012/492920. Epub 2012 Dec 24.
PubMed 23320019Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, Latreche S, Bergaya S, Benhamouda N, Tanchot C, Stockmann C, Combe P, Berger A, Zinzindohoue F, Yagita H, Tartour E, Taieb J, Terme M. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med. 2015 Feb 9;212(2):139-48. doi: 10.1084/jem.20140559. Epub 2015 Jan 19.
PubMed 25601652Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov. 2011 Jun;10(6):417-27. doi: 10.1038/nrd3455.
PubMed 21629292Nickerson ML, Jaeger E, Shi Y, Durocher JA, Mahurkar S, Zaridze D, Matveev V, Janout V, Kollarova H, Bencko V, Navratilova M, Szeszenia-Dabrowska N, Mates D, Mukeria A, Holcatova I, Schmidt LS, Toro JR, Karami S, Hung R, Gerard GF, Linehan WM, Merino M, Zbar B, Boffetta P, Brennan P, Rothman N, Chow WH, Waldman FM, Moore LE. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res. 2008 Aug 1;14(15):4726-34. doi: 10.1158/1078-0432.CCR-07-4921.
PubMed 18676741Gibney GT, Aziz SA, Camp RL, Conrad P, Schwartz BE, Chen CR, Kelly WK, Kluger HM. c-Met is a prognostic marker and potential therapeutic target in clear cell renal cell carcinoma. Ann Oncol. 2013 Feb;24(2):343-349. doi: 10.1093/annonc/mds463. Epub 2012 Sep 28.
PubMed 23022995Mukai S, Yorita K, Kawagoe Y, Katayama Y, Nakahara K, Kamibeppu T, Sugie S, Tukino H, Kamoto T, Kataoka H. Matriptase and MET are prominently expressed at the site of bone metastasis in renal cell carcinoma: immunohistochemical analysis. Hum Cell. 2015 Jan;28(1):44-50. doi: 10.1007/s13577-014-0101-3. Epub 2014 Sep 4.
PubMed 25186085Schiefer AI, Mesteri I, Berghoff AS, Haitel A, Schmidinger M, Preusser M, Birner P. Evaluation of tyrosine kinase receptors in brain metastases of clear cell renal cell carcinoma reveals cMet as a negative prognostic factor. Histopathology. 2015 Dec;67(6):799-805. doi: 10.1111/his.12709. Epub 2015 Jun 7.
PubMed 25847631Sutherland DE, Morrow CE, Florack G, Kretschmer GJ, Baumgartner D, Matas AJ, Najarian JS. Cold storage preservation of islet and pancreas grafts as assessed by in vivo function after transplantation to diabetic hosts. Cryobiology. 1983 Apr;20(2):138-50. doi: 10.1016/0011-2240(83)90003-2. No abstract available.
PubMed 6406150