| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or metastatic clear-cell renal cell carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced or metastatic clear-cell renal cell carcinoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare blinded Independent Radiology Committee (IRC)-adjudicated progression free survival (PFS) of patients treated with CB-839 + cabozantinib (CB-Cabo) versus placebo + cabozantinib (Pbo-Cabo) for advanced or metastatic clear-cell RCC (ccRCC) |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare the overall survival (OS) of patients treated with CB-Cabo vs. Pbo-Cabo
2.To compare the investigator-assessed PFS of patients treated with CB-Cabo vs. Pbo-Cabo |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Informed Consent
a. Ability to provide written informed consent in accordance with federal, local, and institutional guidelines
2. Target Population
a. Documented histological or cytological diagnosis of renal cell carcinoma with a clear-cell component
b. Age ≥ 18 years
c. Karnofsky Performance Score (KPS) ≥ 70% (Attachment 4)
d. Estimated Life Expectancy of at least 3 mo
e. Measurable Disease per RECIST 1.1 as determined by the Investigator (see Attachment 5)
f. One and not more than two prior systemic lines of therapy (monotherapy or combination regimen) for advanced or metastatic RCC
1) Must include either:
i. one anti-angiogenic therapy (any VEGF pathway-targeted agent, used either as monotherapy or as a component of a combination regimen)
– OR –
ii. the combination regimen of nivolumab + ipilimumab
2) Exposure to a prior treatment regimen for ≥4 weeks is considered a prior line of therapy, regardless of reason for its discontinuation (exception: high-dose IL2 will count as prior therapy if >3 doses administered)
i. 4 weeks will be counted from first to last dose for regimens that are intended to be administered on daily schedules (e.g., sunitinib, pazopanib) and from first dose to end of cycle length after last dose for regimens that are intended to be administered in intervals of ≥ 1 week (e.g., one treatment of a Q2W regimen counts as 2 weeks of therapy)
3) Rechallenge with the same agent or regimen will not be considered a new line of therapy, if the patient had not previously discontinued that agent or regimen because of disease progression
4) Systemic adjuvant therapy is considered a prior line of therapy if the patient has disease recurrence on or within 1 year after the last dose of adjuvant therapy
g. The patient must have had radiographic evidence of disease progression on or after the most recent systemic therapy and within 6 mo before randomization
3. Laboratory Findings
a. Serum creatinine ≤ 2.0 × upper limit of normal or calculated creatinine clearance (CCr) ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault equation: CCr = {((l40 – age) x actual body weight)/ (72 x SCr)} x 0.85 (if female)
b. Adequate hematological function, defined as absolute neutrophil count ≥ 1,500/mm3, hemoglobin ≥ 9.0 g/dL, and platelet count ≥ 100,000/mm3. Transfusions and growth factors must not be used within 2 weeks prior to randomization to meet these requirements.
c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 × upper limit of normal.
d. Total bilirubin ≤ 1.5 × the upper limit of normal. For patients with Gilbert’s disease, ≤ 3 mg/dL (≤ 51.3 μmol/L).
e. Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) or 24-hour urine protein < 1 g.
4. Reproductive Status
Female patients of childbearing potential must have a negative serum or urine pregnancy test and if sexually active must agree to contraceptive requirements outlined in Section 10.6.12.2. Male patients who are sexually active with heterosexual partners of childbearing potential must agree to contraceptive requirements and sperm donation restrictions outlined in Section 10.6.12.2.
5. Other Inclusion Criteria
a. Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any prior cancer therapy, unless after discussion with medical monitor adverse events (AEs) are deemed clinically non-significant and/or stable on supportive therapy.
|
|
| E.4 | Principal exclusion criteria |
1.Medical History
a.Prior treatment with cabozantinib (or other MET inhibitor) or CB-839
b.Receipt of any anticancer therapy within the following windows before randomization:
•Small molecule receptor tyrosine kinase inhibitor (TKI) therapy (including investigational) within 2wks or 5 half-lives, whichever longer
•Any type of anticancer antibody/cytotoxic chemotherapy within 4wks
•Radiation therapy for bone metastasis within 2wks, any other external radiation therapy within 4wks, systemic treatment with radionuclides within 6wks before randomization. Patients with clinically relevant ongoing complications (per investigator assessment) from prior radiation therapy.
•Other investigational therapy within 4wks or 5 half-lives, whichever longer.
c.Patients with active and/or untreated central nervous system (CNS) cancer are not eligible. Patients with treated brain metastases (1) must have documented radiographic stability of at least 4wks duration demonstrated on baseline contrast-enhanced CNS imaging (e.g., contrast-enhanced MRI of the brain) prior to randomization and (2) must be symptomatically stable and off of steroids (for the purpose of treating symptoms of brain metastases) for at least 2wks before randomization.
d.Any other current or previous malignancy within the past 3yrs except:
•Adequately treated basal cell or squamous cell skin cancer,
•Carcinoma in situ of the cervix,
•Other neoplasm that, in the opinion of the Principal Investigator and with the agreement of the Medical Monitor, will not interfere with study-specific endpoints
e.Previously identified allergy or hypersensitivity to components of the study treatment formulations. (Note: patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take cabozantinib and are also excluded).
f.Corrected QT interval (QTc) > 500 msec within 1mo before randomization
•Cabozantinib should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with clinically relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances.
2. Concurrent Conditions
a.Unable to receive oral medications or any condition that may prevent adequate absorption of oral study medication including refractory nausea and vomiting, uncontrolled diarrhea, malabsorption, small bowel resection or gastric bypass surgery, use of feeding tubes.
b. Major surgery (e.g., GI surgery) within 6wks before first dose of study treatment or incomplete wound healing from any prior surgery. Patients with clinically relevant ongoing complications (per investigator assessment) from prior surgery are not eligible.
c.The patient has uncontrolled, significant current or recent illness including, but not limited to, the following conditions:
•Cardiovascular disorders:
i.Symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmias
ii.Uncontrolled hypertension defined as sustained BP > 150 mmHg systolic or > 100 mmHg diastolic despite optimal antihypertensive treatment
iii: Stroke (including TIA), myocardial infarction, or other ischemic event within 6 mo before randomization
•GI disorders including those associated with a high risk of perforation or fistula formation:
i.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
ii.Abdominal fistula, GI perforation, bowel obstruction, or intraabdominal abscess within 6mo before randomization
iii.Complete healing of an intra-abdominal abscess must be confirmed before randomization
•Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 tsp (2.5 mL) of red blood, or other history of significant bleeding within 3mo before randomization
•Moderate to severe hepatic impairment (Child-Pugh B or C)
•Lesions invading major pulmonary blood vessels
d.Known active infection with HIV or Hepatitis B or C virus
e.Anticoagulation with warfarin at therapeutic doses is prohibited
•Note: Anticoagulation with therapeutic doses of low molecular weight heparin (LMWH), direct thrombin inhibitors, factor Xa inhibitors, and platelet inhibitors (e.g., clopidogrel) is allowed in patients without brain metastases who are on stable doses for at least 4wks before randomization and have had no complications from the anticoagulation regimen.
•Low-dose aspirin for cardioprotection, and low-dose LMWH are permitted
f. Inability to discontinue proton pump inhibitor use before randomization
g.Any condition including social, psychiatric or medical (including uncontrolled significant concurrent illness) that in opinion of the Investigator could interfere with treatment or protocol-related procedures
h.Patients who are pregnant or lactating |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| IRC-adjudicated PFS per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary inferential PFS comparison between the two treatment arms will take place when a total of 262 events have been observed. |
|
| E.5.2 | Secondary end point(s) |
1. To compare the overall survival (OS) of patients treated with CB-Cabo vs. Pbo-Cabo
2. Investigator-assessed PFS per RECIST v1.1 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| OS is defined as the time from randomization to death due to any cause. For patients alive at the time of analysis, OS will be censored at the time when the patient is last known to be alive. OS analyses will be the similar to the PFS analyses. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| France |
| Germany |
| Italy |
| New Zealand |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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