Study of Cabozantinib in Combination With Atezolizumab compared to Second Novel Hormonal Therapy (NHT) in Subjects with Metastatic Castration-Resistant Prostate Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Exelixis Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 Sep 2020 → ongoing

Decision date (initial)

2024-09-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Exelixis, Inc.

External identifiers

EU CT number

2024-516481-11-00

EudraCT number

2020-000348-77

ClinicalTrials.gov

NCT04446117

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacogenomic, Pharmacokinetic, Efficacy, Pharmacogenetic, Therapy

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

Conditions and MedDRA coding

Metastatic Castration-Resistant Prostate Cancer

Study design 4 periods

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency, Norwegian Medical Products Agency, Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Men with histologically or cytologically confirmed adenocarcinoma of the prostate.
2. Subjects must have had a rising PSA or radiographically progressed 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 ADT 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 otherstudy 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.

Exclusion criteria 15

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: 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 linked 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 intraabdominal 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, druginduced 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, known cirrhosis xi. Requirement for hemodialysis, peritoneal dialysis xii. History of solid organ transplantation xiii. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) - Patients with indwelling cathethers (e.g. PleurX®) are allowed
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 problems from prior surgery are not eligible.
12. Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per ECG within 21 days before randomization.
13. Inability or refusal 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Duration of PFS per RECIST 1.1 per BIRC
2. Duration of OS

Secondary endpoints 1

1. ORR per RECIST 1.1 per BIRC

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Exelixis Inc.

Sponsor organisation

Exelixis Inc.

Address

1851 Harbor Bay Parkway

City

Alameda

Postcode

94502-3010

Country

United States

Scientific contact point

Organisation

Exelixis Inc.

Contact name

Exelixis Medical Affairs

Public contact point

Organisation

Exelixis Inc.

Contact name

Exelixis Medical Affairs

Third parties 15

Locations

9 EU/EEA countries · 33 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 67 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications