MEDI4736 Combinations in Metastatic Renal Cell Carcinoma

NCT02819596 | Completed Phase 2 DMC

• 1 other identifier: 010580QM
• Study Type: interventional
• Target: 69
• Locations: 1 country
• Sites: 1

Brief Summary

This study is being carried out to see if the drugs MEDI4736, Savolitinib and Tremelimumab can be used alone or in combination to reduce the size of tumours in patients with kidney cancer. The drugs being tested in this study have an anti-tumour effect and have been tested in pre-clinical and human studies before. MEDI4736 and tremelimumab work with the immune system to help the body fight against tumour cells with immune cells. Savolitinib works to correct a faulty signal which causes tumour growth. If a patient is eligible for the study and decides to take part, they will be enrolled into one of 3 stages of the study.

• First stage \[CLOSED TO RECRUITMENT\]: aims to find the optimal dose of MEDI4736+savolitinib.
• Second stage \[CLOSED TO RECRUITMENT\]: patients with papillary cell cancer will be treated with MEDI4736+savolitinib. Patients with clear cell cancer will be randomised to one of four treatment arms and receive MEDI4736, savolitinib, MEDI4736+savolitinib, or MEDI4736+tremelimumab.
• Third stage \[NOT YET OPEN TO RECRUITMENT\]: patients will be tested for biomarkers before enrolment, and depending on the results will be allocated to one of 2 treatments (MEDI4736 alone or MEDI4736+tremelimumab) to see if certain biomarkers are linked to drug efficacy.

Conditions

Renal Clear Cell Carcinoma; Renal Papillary Cell Carcinoma

Outcome Measures

Primary Outcomes (4)

• Identify Dose Limiting Toxicity -Phase Ib

  The endpoint of this objective is to identify Dose-Limiting Toxicity that occurs during the DLT assessment phase and is almost certainty/probably dose related and drug related .Toxicity that is clearly and directly related to the primary disease or another aetiology is excluded from this definition.

  6 months

• Overall response (OR) in patients with metastatic clear cell renal cancer

  Overall response rate based on RECIST V1.1 measurements taken at baseline, week 4 and every 8 weeks until disease progression

  18 months

• Overall response (OR) in patients with metastatic Papillary cell renal cancer

  Overall response rate based on RECIST V1.1 measurements taken at baseline, week 4 and every 8 weeks until disease progression

  18 months

• Overall response (OR)in patients with metastatic renal cell cancer -Biomarker enrichment phase

  Overall response rate based on RECIST v1.1 measurements taken at baseline, week 4 and every 8 weeks until disease progression

  11 months

Secondary Outcomes (12)

• De-escalation phase - PK-Cmax measurement

  14 months

• De-escalation phase - PK-Tmax measurement

  14 months

• De-escalation phase -PK AUC (0-t) measurement

  14 months

• De-escalation phase - PK AUCs measurement

  14 months

• De-escalation phase -PK Css measurement

  14 months

Study Arms (4)

Savolitinib

EXPERIMENTAL

600 mg of Savolitinib monotherapy will administered once a day until study completion or withdrawal

Drug: Savolitinib

MEDI4736

EXPERIMENTAL

1500 mg MEDI4736 will be administered every 4 weeks until study completion or withdrawal

Drug: MEDI4736

Savolitinib and MEDI4736

EXPERIMENTAL

Savolitinib and MEDI4736 will be administered at the Recommended Phase 2 dose ascertained in the phase Ib.

Drug: Savolitinib; Drug: MEDI4736

Tremelimumab and MEDI4736

EXPERIMENTAL

Subjects will receive 75 mg of Tremelimumab and 1500 mg medi4736 every 4 weeks for the first four cycles, then 750 mg MEDI4736 every 4 weeks until study completion or withdrawal.

Drug: MEDI4736; Drug: Tremelimumab

Interventions

Savolitinib DRUG

Also known as: Volitinib, AZD6094

Savolitinib; Savolitinib and MEDI4736

MEDI4736 DRUG

Also known as: Durvalumab

MEDI4736; Savolitinib and MEDI4736; Tremelimumab and MEDI4736

Tremelimumab DRUG

Tremelimumab and MEDI4736

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent prior to performing any protocol-related procedures, including study specific screening procedures.
• Age ≥ 18 years at the time of registration/enrolment.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Life expectancy ≥12 weeks
• Histologically confirmed advanced (not amenable to curative surgery or radiation therapy) or metastatic (stage IV) renal cell cancer with a component of either clear cell cancer or papillary cancer. Patients with a component of both must be enrolled into the cohort with the predominant tumour type.
• Clear cell renal cancer patients must have experienced progressive disease after exposure to Vascular Endothelial growth rate (VEGF) targeted therapy.
• Sarcomatoid cell renal cancer patients must have experienced progressive disease after exposure to VEGF targeted therapy.
• Papillary cell renal cancer patients must be considered to be VEGF treatment naive or treatment refractory to be eligible.
• Evidence of measurable disease as per RECIST v1.1 (i.e., ≥1 malignant tumour mass that can be accurately measured in at least 1 dimension ≥ 20 mm with conventional computerized tomography CT Scan or Magnetic Resonance Imaging (MRI), or ≥10 mm with spiral CT scan using a 5 mm or smaller contiguous reconstruction algorithm). Bone lesions, ascites, peritoneal carcinomatosis or miliary lesions, pleural or pericardial effusions, lymphangitis of the skin or lung, cystic lesions, or irradiated lesions are not considered measurable.
• Adequate normal organ, marrow and coagulation function as defined by the following criteria:
• Representative formalin-fixed paraffin-embedded (FFPE) tumour block with an associated anonymised pathology report must be available for central testing and determined to be evaluable for tumour assessment of PD-L1 and Met. PD-L1 and Met related testing will be required prior to study entry only for the biomarker enrichment phase of the trial. (every effort should be made to obtain FFPE blocks however unstained fresh tissue slides and core needle biopsies will suffice).
• Patients with known tumour thrombus or deep vein thrombosis (DVT) are eligible if stable on low molecular weight heparin (LMWH) for ≥ 4 weeks.
• Negative serum or urine pregnancy test within 2 weeks prior to the first dose of IMP (for female patients of childbearing potential only).
• Agreement to use adequate contraceptive measures (Section 6.18).
• Ability to swallow and retain oral medications.

You may not qualify if:

• Participation in another clinical study with an investigational product within 28 days prior to enrolment in the study.
• Any previous treatment with an anti-programmed death-1 (PD-1), or anti-PD-L1 therapeutic antibody (including MEDI4736), CD137 agonists, c-MET inhibitors or pathway-targeting agents, or CTLA-4. Patients with limited c-MET inhibitor exposure must be discussed with the study medical monitor.
• Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumour embolization, monoclonal antibodies) within 2 weeks or five half-lives of the anti-cancer therapy prior to the first dose of study drug, or radical radiotherapy within 4 weeks prior to the first dose of study drug.
• Patients receiving strong inducers of CYP3A4, strong inhibitors of CYP3A4 or CYP1A2 or CYP3A4 substrates which have a narrow therapeutic range within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort) are excluded from enrolment in the study (see Appendix I).
• Currently receiving treatment with therapeutic doses of warfarin sodium. LMWH is allowed.
• Current or prior use of immunosuppressive medication within 21 days before the first dose of MEDI4736 or tremelimumab, 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.
• Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin \[IL\] -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 MEDI4736 or tremelimumab or anticipation that such a live, attenuated vaccine will be required during the study.
• Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids.
• History of another primary malignancy other than renal cell carcinoma within 3 years prior to Cycle 1, Day 1 with the exception of:
• Malignancy treated with curative intent and with no known active disease ≥ 3 years before the first dose of study drug and of low potential risk for recurrence.
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
• Adequately treated carcinoma in situ without evidence of disease e.g. cervical cancer in situ or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 and PSA \<10ng/mL undergoing active surveillance and treatment naive). Patients on surveillance for low risk prostate cancer are also eligible - please discuss with medical monitor.
• Mean resting QT interval corrected for heart rate (QTc) \>470ms for women and \>450ms for men calculated from triplicate electrocardiograms (ECGs) using Fridericia's correction.
• Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome).

Sponsors & Collaborators

• Queen Mary University of London: lead
• Vall d'Hebron Institute of Oncology: collaborator
• AstraZeneca: collaborator

Study Sites (1)

Thomas Powles

London, EC1M 6BQ, United Kingdom

Location

Related Publications (4)

• Powles T et al. CALYPSO: A three-arm randomized phase II study of durvalumab alone or with savolitinib or tremelimumab in previously treated advanced clear cell renal cancer. Journal of Clinical Oncology 40, no. 17_suppl (June 10, 2022) LBA4503-LBA4503

  RESULT

• Suarez C, Larkin JMG, Patel P, Valderrama BP, Rodriguez-Vida A, Glen H, Thistlethwaite F, Ralph C, Srinivasan G, Mendez-Vidal MJ, Hartmaier R, Markovets A, Prendergast A, Szabados B, Mousa K, Powles T. Phase II Study Investigating the Safety and Efficacy of Savolitinib and Durvalumab in Metastatic Papillary Renal Cancer (CALYPSO). J Clin Oncol. 2023 May 10;41(14):2493-2502. doi: 10.1200/JCO.22.01414. Epub 2023 Feb 21.

  PMID: 36809050 RESULT

• Suarez Rodriguez et al. Overall survival results for durvalumab and savolitinib in metastatic papillary renal cancer. Journal of Clinical Oncology 2020 38:6_suppl, 619-619.

  RESULT

• Suarez Rodriguez et al Clinical activity of durvalumab and savolitinib in MET-driven, metastatic papillary renal cancer. J Clin Oncol 39, 2021 (suppl 15; abstr 4511).

  RESULT

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine; durvalumab; tremelimumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 22, 2016
• First Posted: June 30, 2016
• Study Start: May 3, 2016
• Primary Completion: July 17, 2024
• Study Completion: July 17, 2024
• Last Updated: November 4, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)