Clinical trial NCT03149822: Study of Pembrolizumab and Cabozantinib in Patients With Metastatic Renal Cell Carcinoma
Official title: Phase I/II Study of Pembrolizumab and Cabozantinib in Patients With Metastatic Renal Cell Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Metastatic Renal Cell Carcinoma
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2017-05-11
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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. 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.

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.

Eligibility criteria: Inclusion Criteria:

1. Subjects must have histological or cytological documentation of renal cell carcinoma
2. Subjects must have locally advanced, recurrent, or metastatic disease.
3. Be willing and able to provide written informed consent/assent for the trial.
4. Stated willingness to complywith all study procedures and be available for the duration of the trial.
5. Be ≥ 18 years of age on day of signing informed consent.
6. Have measurable or evaluable disease based on RECIST 1.1.
7. 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.
8. 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.
9. Have a performance status of 0 or 1 on the ECOG Performance Scale.
10. Demonstrate adequate organ function as defined by desired lab values.
11. 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.
12. 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.
13. 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.

Exclusion Criteria:

1. 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.
2. 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.
3. Has a known history of active TB (Bacillus Tuberculosis)
4. Has had prior treatment with pembrolizumab.
5. Has had prior treatment with cabozantinib.
6. 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.

   - Note: Subjects with stable, treated hypothyroidism or adrenal insufficiency may qualify for the study
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. Has history of solid organ transplantation.
14. Has history of osteonecrosis of the jaw.
15. Has history of reversible posterior leukoencephalopathy syndrome.
16. Has history of wound dehiscence or complications requiring medical intervention within 6 months of study entry.
17. Has history of (non-infectious) pneumonitis that required steroids or active, non- infectious pneumonitis.
18. Has an active infection requiring systemic therapy with IV antibiotics.
19. Has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

    1. 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.
    2. 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.
    3. Has clinically significant hematuria, hematemesis, or hemoptysis of \> 0.5 teaspoon within 3 months before randomization.
    4. 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.
    5. Lesions invading major pulmonary blood vessels.
20. 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.
21. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
22. 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.
23. Has an inability to swallow tablets or capsules.
24. Has a previously identified allergy or hypersensitivity to components of the study treatment formulations.
25. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
26. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
27. 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.

Primary outcomes:
measure: Efficacy of Pembrolizumab and Cabozantinib Based on Objective Response Rate
timeFrame: Beginning of study to end of study, up to 5 years
Secondary outcomes:
measure: Maximally Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)
timeFrame: Throughout Cycle 1, up to 21 days
measure: Dose Limiting Toxicities
timeFrame: Throughout Cycle 1, up to 21 days
measure: Progression-Free Survival
timeFrame: Beginning of study to end of study, or death, whichever comes first, up to 5 years
measure: Overall Survival
timeFrame: Beginning of study to end of study, or death, whichever comes first, up to 5 years
measure: Disease Control Rate (DCR), AKA Clinical Benefit Rate (CBR)
timeFrame: Beginning of study to end of study, or death, whichever comes first, up to 5 years
measure: Duration of Response
timeFrame: Time of first response as measured by RECIST 1.1 to time of progression or death, whichever comes first, up to 5 years
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Colorado Springs
country: United States
facility: Memorial Hospital Central
state: Colorado
city: Fort Collins
country: United States
facility: Poudre Valley Hospital
state: Colorado
city: Highlands Ranch
country: United States
facility: Highlands Ranch Hospital
state: Colorado
city: Lone Tree
country: United States
facility: UCHealth Lone Tree Medical Center
state: Colorado
Study officials:
affiliation: University of Colorado, Denver
name: Elaine Lam, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Philips 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.
citation: Hato 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.
citation: Massari 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.
citation: Motzer 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.
citation: Ko 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.
citation: Tartour 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.
citation: Terme 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.
citation: Voron 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.
citation: Carmeliet 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.
citation: Nickerson 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.
citation: Gibney 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.
citation: Mukai 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.
citation: Schiefer 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.
citation: Sutherland 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.
citation: Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, Feldman DR, Olencki T, Picus J, Small EJ, Dakhil S, George DJ, Morris MJ. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. J Clin Oncol. 2017 Feb 20;35(6):591-597. doi: 10.1200/JCO.2016.70.7398. Epub 2016 Nov 14.
citation: Harshman LC, Choueiri TK. Targeting the hepatocyte growth factor/c-Met signaling pathway in renal cell carcinoma. Cancer J. 2013 Jul-Aug;19(4):316-23. doi: 10.1097/PPO.0b013e31829e3c9a.
citation: Choueiri TK, Pal SK, McDermott DF, Morrissey S, Ferguson KC, Holland J, Kaelin WG, Dutcher JP. A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol. 2014 Aug;25(8):1603-8. doi: 10.1093/annonc/mdu184. Epub 2014 May 14.