| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castration-Resistant Prostate Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076506 |
| E.1.2 | Term | Castration-resistant prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 evaluate the efficacy of cabozantinib in combination with atezolizumab versus second NHT (abiraterone or enzalutamide) in subjects with mCRPC who have previously received one and only one NHT (eg, abiraterone, apalutamide, darolutamide, or enzalutamide) to treat mCSPC, M0 CRPC, and/or mCRPC, and who have measurable visceral disease or measurable extrapelvic adenopathy. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Men with histologically or cytologically confirmed adenocarcinoma of the prostate.
2. Subjects must have had a rising PSA or radiographically progresses on their prior treatment with one, and only one, NHT (eg, abiraterone, apalutamide, darolutamide, or enzalutamide) for castration-sensitive locally advanced (T3 or T4) or metastatic castration-sensitive prostate cancer, M0 CRPC, and/or mCRPC.
3. Bilateral orchiectomy or ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist/antagonist (surgical or medical castration), with serum testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening.
4. Measurable (extrapelvic soft tissue) metastatic disease per Investigator assessment as defined by at least one of the following:
a. Measurable visceral (eg, adrenal, kidney, liver, lung, pancreas, spleen) disease per RECIST 1.1, OR
b. Measurable extrapelvic adenopathy (ie, adenopathy above the aortic bifurcation).
5. Progressive disease at study entry as defined by at least one of the following two criteria:
a. Prostate specific antigen (PSA) progression defined by a minimum of 2 rising PSA values from 3 or 4 most recent consecutive assessments with an interval of at least 7 days between assessments.
b. Soft tissue disease progression (PD) in the opinion of the Investigator.
6. Age ≥ 18 years old or meeting country definition of adult, whichever is older, on the day of consent.
7. ECOG performance status score of 0 or 1.
8. Recovery to baseline or ≤ Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) v5 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy in the opinion of the Investigator.
9. Adequate organ and marrow function, based upon all of the following laboratory assessments from samples obtained within 21 days before randomization:
a. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 × 109/L) without granulocyte colony stimulating factor support within 2 weeks before screening laboratory sample collection.
b. Platelets ≥ 100,000/mm3 (≥ 100 × 109/L) without transfusion within 2 weeks before screening laboratory sample collection.
c. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without transfusion within 1 week before screening laboratory sample collection.
d. Serum bilirubin ≤ 1.5 × upper limit of normal (ULN)
e. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) both ≤ 3 × ULN. Subjects with known hepatic metastasis may enroll with serum ALT and AST both ≤ 5 × ULN.
f. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40 mL/min using the Cockcroft-Gault equation: (140 – age) × weight (kg)/(serum creatinine [mg/dL] × 72).
g. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine protein < 1 g.
h. Negative hepatitis B surface antigen (HBsAg) test
i. Negative hepatitis C virus (HCV) antibody test, or positive HCV antibody test followed by a negative HCV RNA test and no ongoing anti-HCV therapy.
10. Understanding and ability to comply with the protocol requirements, including scheduled visits, treatment plan, laboratory tests, and all other study procedures. Evidence of a signed and dated ICF, indicating that the subject has been informed of all pertinent aspects of the study, prior to any screening assessments except those procedures performed as standard of care within the screening window.
11. Sexually active fertile subjects and their female partners must agree to use highly effective methods of contraception during the course of the study and for 4 months (16 weeks) after the last dose of cabozantinib in the experimental arm (cabozantinib + atezolizumab), 3 weeks after the last dose of abiraterone (control arm), or 3 months (12 weeks) after the last dose of enzalutamide (control arm). A barrier contraceptive method (eg, condom) is also required. In addition, men must agree not to donate sperm during these same periods.
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| E.4 | Principal exclusion criteria |
1. Only evidence of metastasis is adenopathy below the aortic bifurcation, non measurable soft tissue (visceral or adenopathic) disease per RECIST 1.1, or bone-only disease.
2. Any prior systemic nonhormonal therapy initiated for the treatment of mCRPC.
3. Receipt of abiraterone within 1 week; cyproterone within 10 days; or receipt of flutamide, nilutamide, bicalutamide, enzalutamide, or other androgen-receptor inhibitors within 2 weeks before randomization.
4. Radiation therapy within 4 weeks (2 weeks for bone metastases) prior to randomization. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
5. Known brain metastases (symptomatic or non-symptomatic) or cranial epidural disease unless adequately treated with radiotherapy, radiosurgery, or major surgery and clinically stable for at least 4 weeks prior to randomization.
6. Symptomatic or impending spinal cord compression or cauda equina syndrome.
7. Concomitant anticoagulation with oral anticoagulants including, but not limited to, platelet inhibitors (eg, clopidogrel or ticagrelor), warfarin, dabigatran, and betrixaban, except for those specified in the protocol.
8. Administration of a live, attenuated vaccine within 30 days prior to randomization. The use of inactivated vaccines for the prevention of infectious disease is permitted.
9. Systemic treatment with, or any condition requiring, either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to randomization. Subjects with brain metastases requiring systemic corticosteroid at any dose are not eligible.
10. Uncontrolled, significant intercurrent or recent illness that may impede analysis of safety data, including, but not limited to, the following conditions:
a. Cardiovascular and cardiac disorders
b. Neuropsychiatric disorder likely to impede with ability to give informed consent or comply with protocol requirements.
c. GI disorders, including those affecting absorption or associated with a high risk of perforation or fistula formation:
i. Tumors invading the GI tract, active peptic ulcer disease, acute pancreatitis, acute obstruction of the pancreatic or biliary duct, appendicitis, cholangitis, cholecystitis, diverticulitis, gastric outlet obstruction, or IBD
ii. Abdominal fistula, bowel obstruction, GI perforation, or intra-abdominal abscess within 6 months before randomization
d. Hemoptysis of > 2.5 ml of red blood, clinically significant hematuria, hematemesis, coagulopathy, or other history of significant bleeding within 3 months before randomization.
e. Known cavitating pulmonary lesions or known endobronchial disease manifestation.
f. Lesions invading major pulmonary blood vessels.
g. Other clinically significant disorders, such as:
i. Any active, known or suspected autoimmune disease
ii. Any active infection requiring systemic treatment.
iii. Known HIV, AIDS-related illness.
iv. Active tuberculosis.
v. Known history of COVID-19 unless the subject has shown recovery from the disease at least 30 days prior to randomization.
vi. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
vii. Serious non-healing wound/ulcer/bone fracture per Investigator judgment.
viii. Clinically significant malabsorption syndrome per Investigator judgment.
ix. Pharmacologically uncompensated, symptomatic hypothyroidism.
x. Moderate to severe hepatic impairment or known cirrhosis.
xi. Requirement for hemodialysis or peritoneal dialysis.
xii. History of solid organ transplantation
11. Major surgery within 4 weeks prior to randomization. Minor surgeries within 10 days prior to randomization. Subjects must have complete wound healing from major surgery or minor surgery before randomization. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
12. Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per electrocardiogram (ECG) within 21 days before randomization.
13. Inability or unwillingness to swallow tablets or receive IV administration.
14. Previously identified allergy or hypersensitivity to components of the study treatment formulations or history of severe infusion-related reactions to monoclonal antibodies. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption are also excluded.
15. Any other active malignancy at time of randomization or diagnosis of another malignancy within 2 years prior to randomization that requires active treatment, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, or carcinoma in situ of the breast.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Duration of PFS per RECIST 1.1 per BIRC
• Duration of OS |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• The primary analysis of PFS is event-driven and will be conducted after at least 202 events have been observed in the PITT population.
• The primary analysis of OS is event-driven and will be conducted after at least 340 deaths have been observed in the ITT population. |
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| E.5.2 | Secondary end point(s) |
| • ORR per RECIST 1.1 per BIRC |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At time of data cutoff, the proportion of subjects for whom the best overall response is a CR or PR as assessed by the BIRC per RECIST 1.1, which is confirmed by a subsequent visit ≥ 28 days later. |
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| 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 | Yes |
| 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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 96 |
| 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 |
| Argentina |
| Chile |
| Singapore |
| Ukraine |
| Taiwan |
| Australia |
| Brazil |
| Canada |
| Georgia |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Czechia |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Poland |
| Portugal |
| Spain |
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| 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
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| The last scheduled visit or scheduled procedure for the last subject (including Maintenance Phase assessments). |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 16 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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