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MEDI4736 Combinations in Metastatic Renal Cell Carcinoma (CALYPSO)

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ClinicalTrials.gov Identifier: NCT02819596
Recruitment Status : Recruiting
First Posted : June 30, 2016
Last Update Posted : August 28, 2017
Sponsor:
Collaborators:
Vall d'Hebron Institute of Oncology
AstraZeneca
Information provided by (Responsible Party):
Queen Mary University of London

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 [RECRUITING]: 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 3 treatments (MEDI4736, savolitinib, or MEDI4736+tremelimumab) to see if certain biomarkers are linked to drug efficacy.

Condition or disease Intervention/treatment Phase
Renal Clear Cell Carcinoma Renal Papillary Cell Carcinoma Drug: Savolitinib Drug: MEDI4736 Drug: Tremelimumab Phase 2

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 195 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: MEDI4736 Combinations in Metastatic Renal Cell Carcinoma
Actual Study Start Date : January 2017
Estimated Primary Completion Date : October 2018
Estimated Study Completion Date : September 2019


Arm Intervention/treatment
Experimental: Savolitinib
600 mg of Savolitinib monotherapy will administered once a day until study completion or withdrawal
Drug: Savolitinib
Other Names:
  • Volitinib
  • AZD6094

Experimental: MEDI4736
1500 mg MEDI4736 will be administered every 4 weeks until study completion or withdrawal
Drug: MEDI4736
Other Name: Durvalumab

Experimental: Savolitinib and MEDI4736
Savolitinib and MEDI4736 will be administered at the Recommended Phase 2 dose ascertained in the phase Ib.
Drug: Savolitinib
Other Names:
  • Volitinib
  • AZD6094

Drug: MEDI4736
Other Name: Durvalumab

Experimental: Tremelimumab and MEDI4736
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
Other Name: Durvalumab

Drug: Tremelimumab



Primary Outcome Measures :
  1. Identify Dose Limiting Toxicity -Phase Ib [ Time Frame: 6 months ]
    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.

  2. Overall response (OR) in patients with metastatic clear cell renal cancer [ Time Frame: 18 months ]
    Overall response rate based on RECIST V1.1 measurements taken at baseline, week 4 and every 8 weeks until disease progression

  3. Overall response (OR) in patients with metastatic Papillary cell renal cancer [ Time Frame: 18 months ]
    Overall response rate based on RECIST V1.1 measurements taken at baseline, week 4 and every 8 weeks until disease progression

  4. Overall response (OR)in patients with metastatic renal cell cancer -Biomarker enrichment phase [ Time Frame: 11 months ]
    Overall response rate based on RECIST v1.1 measurements taken at baseline, week 4 and every 8 weeks until disease progression


Secondary Outcome Measures :
  1. De-escalation phase - PK-Cmax measurement [ Time Frame: 14 months ]
    Measurement of Cmax for MEDI4736 and savolitinib

  2. De-escalation phase - PK-Tmax measurement [ Time Frame: 14 months ]
    Measurement of tmax for MEDI4736 and savolitinib

  3. De-escalation phase -PK AUC (0-t) measurement [ Time Frame: 14 months ]
    Measurement of AUC(0-t)for MEDI4736 and savolitinib

  4. De-escalation phase - PK AUCs measurement [ Time Frame: 14 months ]
    Measurement of AUCs for MEDI4736 and savolitinib

  5. De-escalation phase -PK Css measurement [ Time Frame: 14 months ]
    Measurement of Css max for MEDI4736 and savolitinib

  6. De-escalation phase -PK Css min measurement [ Time Frame: 14 months ]
    Measurement of Css min. for MEDI4736 and savolitinib

  7. Expansion Phase (IIa) -Identify Progression free survival (PFS) [ Time Frame: 18 months ]
    PFS defined as the time from the date of registration to the date of the first documented tumour progression as per RECIST V1.1 or death from any cause , whichever occurs first

  8. Expansion Phase (IIa) -Identify overall Survival (OS) [ Time Frame: 18 months ]
    OS defined as the time from study entry to death from any cause.All deaths will be included whether they occur on study or following treatment discontinuation. For patients who have not died, overall survival will be censored at the date of last contact

  9. Expansion Phase (IIa) -Identify duration of response [ Time Frame: 18 months ]
    OS defined as the time from study entry to death from any cause.All deaths will be included whether they occur on study or following treatment discontinuation. For patients who have not died, overall survival will be censored at the date of last contact

  10. Biomarker positive patient analysis [ Time Frame: 11 months ]
    Patients that have test positive for C-met or PD-L1 alterations;OS defined as the time from study entry to death from any cause.All deaths will be included whether they occur on study or following treatment discontinuation. For patients who have not died, overall survival will be censored at the date of last contact

  11. Biomarker positive patient analysis [ Time Frame: 11 months ]
    Patients that have test positive for C-met or PD-L1 alterations; PFS defined as the time from the date of registration to the date of the first documented tumour progression as per RECIST V1.1 or death from any cause , whichever occurs first



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent prior to performing any protocol-related procedures, including study specific screening procedures.
  2. Age ≥ 18 years at the time of study entry.
  3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  4. Life expectancy ≥12 weeks
  5. 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.

    1. Clear cell renal cancer patients must have experienced progressive disease after exposure to Vascular Endothelial growth rate (VEGF) targeted therapy.
    2. Papillary cell renal cancer patients must be considered to be VEGF treatment naive or treatment refractory to be eligible.
  6. Evidence of measurable disease (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.
  7. Adequate normal organ, marrow and coagulation function as defined by the following criteria:

    1. Haemoglobin ≥ 9.0g/dL
    2. Absolute neutrophil count (ANC) ≥1.5 x 109/L (≥1500/L) without growth factor support
    3. Platelet count ≥ 100 x 109 /L (≥100,000/L)
    4. Total serum bilirubin ≤1.5 x institutional upper limit of normal (ULN) (this will not apply to subjects with confirmed Gilbert's syndrome [persistent or recurrent hyperbilirubinaemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology], who will be allowed only in consultation with their physician.
    5. Serum transaminases (AST/ALT) ≤2.5 x the institutional ULN.
    6. Glomerular filtration rate (GFR)FR ≥40mL/min as assessed using the standard methodology at the investigating sites (e.g. by Cockroft-Gault).
    7. International Normalisation Ration (INR) <1.5 x institutional ULN or activated partial thromboplastin time (aPTT) <1.5 x institutional ULN. This applies only to patients who do not receive therapeutic anti-coagulation.
  8. 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)
  9. Patients with known tumour thrombus or deep vein thrombosis (DVT) are eligible if stable on low molecular weight heparin (LMWH) for ≥ 4 weeks.
  10. Negative serum or urine pregnancy test within 2 weeks prior to the first dose of IMP (for female patients of childbearing potential only). Non-childbearing potential is defined as:

    1. Post-menopausal defined as aged 50 years of age and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments OR
    2. Documented irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation OR
    3. <50 years of age who have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with Luteinizing hormone (LH) and Follicle Stimulating Hormone (FSH) levels within local institution post-menopausal ranges
  11. Agreement to use adequate contraceptive measures (Section 6.18).
  12. Ability to swallow and retain oral medications.
  13. Willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled visits and examinations including follow up.

Exclusion Criteria:

  1. Participation in another clinical study with an investigational product within 28 days prior to enrolment in the study.
  2. 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.
  3. 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.
  4. 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).
  5. Currently receiving treatment with therapeutic doses of warfarin sodium. LMWH is allowed.
  6. 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.
  7. 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.
  8. 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.
  9. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids.
  10. History of another primary malignancy other than renal cell carcinoma within 3 years prior to Cycle 1, Day 1 with the exception of:

    1. 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.
    2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
    3. 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.
  11. Mean resting QT interval corrected for heart rate (QTc) >470ms calculated from triplicate electrocardiograms (ECGs).
  12. 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).
  13. Any unresolved toxicity of CTCAE grade >2 from previous anti-cancer therapy. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by the IMP may be included e.g. hearing loss, peripheral neuropathy etc.
  14. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1.
  15. 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.
  16. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) or history of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug
  17. History of primary immunodeficiency
  18. History of allogeneic prior allogeneic stem cell or solid organ transplant
  19. History of hypersensitivity to MEDI4736, tremelimumab, or any excipient or history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  20. History of hypersensitivity to savolitinib and its excipients.
  21. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension (SBP>160mmHg or Diastolic blood pressure >100mmHg, patients with values above these levels must have their blood pressure controlled with medication prior to starting treatment), unstable angina pectoris, cardiac arrhythmia, or any factors that increase the risk of QTc prolongation, any clinically important abnormalities in rhythm, conduction or morphology of resting ECGs, active peptic ulcer disease or gastritis, Type I diabetes mellitus, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
  22. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to enrolment, Patients with a known left ventricular ejection fraction (LVEF) < 40% will be excluded.
  23. Major surgical procedure within 4 weeks prior to enrolment, minor surgical procedure within 7 days of enrolment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis
  24. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field (fibrosis) is permitted).
  25. Active tuberculosis or known history of previous clinical diagnosis of tuberculosis.
  26. History of leptomeningeal carcinomatosis
  27. Female subjects who are pregnant or breast-feeding
  28. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02819596


Contacts
Contact: Thomas Powles, MD 02078825085 bci-calypso@qmul.ac.uk
Contact: CECM Trials Team bci-calypso@qmul.ac.uk

Locations
Spain
Hospital del Mar - Parc de Salut Mar Not yet recruiting
Barcelona, Spain, 08003
Vall d'Hebron Institute of Oncology Recruiting
Barcelona, Spain, 08035
Contact: Cristina Suarez       crsuarez@vhebron.net   
Hospital Clínic de Barcelona Not yet recruiting
Barcelona, Spain, 08036
Hospital Universitario Reina Sofía Not yet recruiting
Córdoba, Spain, 14004
Hospital General Universitario Gregorio Marañón Not yet recruiting
Madrid, Spain, 28007
Fundación de Investigación Biomédica del Hospital Clínico San Carlos Not yet recruiting
Madrid, Spain, 28040
Hospital Universitario Central de Asturias Not yet recruiting
Oviedo, Spain, 33011
Fundación Ramón Domínguez Not yet recruiting
Santiago de Compostela, Spain, 15706
Hospital Universitario Virgen del Rocio Not yet recruiting
Sevilla, Spain, 41013
IVO Instituto Valenciano de Oncología Not yet recruiting
Valencia, Spain, 46009
United Kingdom
Broomfield Hospital -Mid Essex NHS trust Recruiting
Chelmsford, United Kingdom, CM1 7ET
Contact: Gopalakrishnan Srinivasan       Gopalakrishnan.Srinivasan@meht.nhs.uk   
Beatson West of Scotland Cancer Centre Recruiting
Glasgow, United Kingdom, G12 0YN
Contact: Hilary Glen       Hilary.Glen@ggc.scot.nhs.uk   
Leeds Institute of Cancer and Pathology & St James's Institute of Oncology Recruiting
Leeds, United Kingdom, LS9 7TF
Contact: Christy Ralph       c.ralph@leeds.ac.uk   
Thomas Powles Recruiting
London, United Kingdom, EC1M 6BQ
Contact: Thomas Powles    +44(0)2078825085    bci-calypso@qmul.ac.uk   
Contact    02078825085    bci-calypso@qmul.ac.uk   
Royal Marsden NHS Foundation Trust Recruiting
London, United Kingdom, SW3 6JJ
Contact: James Larkin       james.larkin@rmh.nhs.uk   
Imperial College Healthcare NHS Trust Not yet recruiting
London, United Kingdom
Contact: Naveed Sarwar       naveed.sarwar@imperial.nhs.uk   
The Christie NHS Foundation Trust Recruiting
Manchester, United Kingdom, M20 4BX
Contact: Fiona Thistlethwaite       fiona.thistlethwaite@christie.nhs.uk   
Nottingham University Hospitals NHS Trust Recruiting
Nottingham, United Kingdom, NG5 1PB
Contact: Patel Poulam       poulam.patel@nottinhgam.ac.uk   
Sponsors and Collaborators
Queen Mary University of London
Vall d'Hebron Institute of Oncology
AstraZeneca

Responsible Party: Queen Mary University of London
ClinicalTrials.gov Identifier: NCT02819596     History of Changes
Other Study ID Numbers: 010580QM
First Posted: June 30, 2016    Key Record Dates
Last Update Posted: August 28, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Renal Cell
Adenomyoepithelioma
Adenocarcinoma, Clear Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Neoplasms, Complex and Mixed
Antibodies, Monoclonal
Tremelimumab
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents