Clinical Trials /

A Multi-centre Study to Assess the Safety, Tolerability, and Pharmacokinetics of Capivasertib (AZD5363) in Combination With Novel Agents in Patients With Metastatic Prostate Cancer

NCT04087174

Description:

This is a Phase Ib, open-label, multi-centre study to determine the safety, tolerability and pharmacokinetics (PK) of capivasertib when given in combination with novel agents (enzalutamide or abiraterone) to inform the selection of capivasertib dose regimens for each combination for further clinical evaluation when given to patients with metastatic castration resistant prostate cancer (CRPC). The study design allows an exploration of different doses with intensive safety monitoring to ensure the safety of the patients.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Multi-centre Study to Assess the Safety, Tolerability, and Pharmacokinetics of Capivasertib (AZD5363) in Combination With Novel Agents in Patients With Metastatic Prostate Cancer
  • Official Title: A Phase I, Open-label, Multi-centre Study to Assess the Safety, Tolerability, and Pharmacokinetics of Capivasertib (AZD5363) in Combination With Novel Agents in Patients With Metastatic Castration Resistant Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: D3618C00002
  • NCT ID: NCT04087174

Conditions

  • Prostate Cancer

Interventions

DrugSynonymsArms
CapivasertibAZD5363Part A1: Capivasertib + enzalutamide
EnzalutamidePart A1: Capivasertib + enzalutamide
AbirateronePart A2: Capivasertib + abiraterone

Purpose

This is a Phase Ib, open-label, multi-centre study to determine the safety, tolerability and pharmacokinetics (PK) of capivasertib when given in combination with novel agents (enzalutamide or abiraterone) to inform the selection of capivasertib dose regimens for each combination for further clinical evaluation when given to patients with metastatic castration resistant prostate cancer (CRPC). The study design allows an exploration of different doses with intensive safety monitoring to ensure the safety of the patients.

Detailed Description

      The study will be conducted on multiple centers (≤10) in USA and Spain. The study design
      allows an exploration of different doses with intensive safety monitoring to ensure the
      safety of the patients.

      The two planned combination treatments during Part A of this study are:

      Part A1: Capivasertib and enzalutamide Part A2: Capivasertib and abiraterone Part B will
      include any optional dose expansion cohorts based on Safety Review Committee (SRC) review of
      data from Part A of this study.

      The study will include up to approximately 87 evaluable patients, divided among the 4 study
      parts as follows:

      Part A1: Up to approximately 36 patients (up to four dose levels with up to approximately 9
      patients per dose level).

      Part B1: Up to approximately 12 patients. Part A2: Up to approximately 27 patients (up to
      three dose levels with up to approximately 9 patients per dose level). Part B2: Up to
      approximately 12 patients.
    

Trial Arms

NameTypeDescriptionInterventions
Part A1: Capivasertib + enzalutamideExperimentalFrom day 1 to day 28 of this study treatment, patients will continuously enroll on a starting dose of capivasertib in combination with 160 mg enzalutamide.
  • Capivasertib
  • Enzalutamide
Part A1: Capivasertib dose level 1 + enzalutamideExperimentalOn day 29 of the treatment, patients will escalate the capivasertib dose to dose level+1 along with 160 mg enzalutamide.
  • Capivasertib
  • Enzalutamide
Part A1: Capivasertib dose level 2 + enzalutamideExperimentalOn day 29 of the treatment, patients will escalate the capivasertib dose to dose level+2 along with 160 mg enzalutamide.
  • Capivasertib
  • Enzalutamide
Part A2: Capivasertib + abirateroneExperimentalPatients will continuously enroll on a starting dose of capivasertib in combination with 1000 mg abiraterone.
  • Capivasertib
  • Abiraterone
Part B1: Capivasertib + enzalutamideExperimentalThis optional expansion will treat patients at the recommended dose regimen of capivasertib and enzalutamide.
  • Capivasertib
  • Enzalutamide
Part B2: Capivasertib + abirateroneExperimentalThis optional expansion will treat patients at the recommended dose regimen of capivasertib and abiraterone.
  • Capivasertib
  • Abiraterone

Eligibility Criteria

        Inclusion Criteria:

          1. Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the informed consent form (ICF) and in this
             protocol prior to any mandatory study-specific procedures, sampling, and analyses.

          2. Males aged 18 years and older at the time of signing the ICF.

          3. Patients with documented evidence of metastatic CRPC who may benefit from treatment
             with capivasertib or for whom no alternative approved therapy is available.

          4. World Health Organization (WHO) performance status 0 to 2 with no deterioration over
             the previous 2 weeks and minimum life expectancy of 12 weeks, as assessed at day 1.

          5. Patients must be able to swallow and retain oral medication.

          6. Agreement to remain abstinent (refrain from heterosexual intercourse) or use
             contraceptive measures, and agreement to refrain from donating sperm.

               -  Sterilisation (with the appropriate post-vasectomy documentation of the absence
                  of sperm in the ejaculate).

               -  Patients should use barrier contraception (ie, condoms) from the time of
                  screening until 16 weeks after discontinuation of study treatment. It is not
                  known whether the preclinical changes seen in the male animal reproductive
                  organs, after treatment with capivasertib, will be fully reversible or will
                  permanently affect the ability to produce healthy sperm following treatment.
                  Therefore, if patients wish to father children they should be advised to arrange
                  for collection of sperm samples prior to the start of study treatment.

        Exclusion Criteria:

          1. Previous enrolment in the present study.

          2. Prior enzalutamide therapy in the last 8 weeks.

          3. Treatment with any of the following:

               -  Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment.

               -  Any investigational agents or study drugs from a previous clinical study within
                  30 days of the first dose of study treatment.

               -  Any other chemotherapy, immunotherapy, immunosuppressant medication (other than
                  corticosteroids) or anti-cancer agents within 3 weeks of the first dose of study
                  treatment, except hormonal therapy with luteinising hormone-releasing hormone
                  (LHRH) analogues for medical castration in patients with prostate cancer, which
                  are permitted.

               -  Potent inhibitors or inducers or substrates of CYP3A4 within 2 weeks before the
                  first dose of study treatment (3 weeks for St. John's wort) or sensitive
                  substrates of CYP3A4, CYP2C9 and/or CYP2D6 with a narrow therapeutic window
                  within 1 week prior to the first dose of study treatment.

          4. Major surgery (excluding placement of vascular access) within 4 weeks of the first
             dose of study treatment.

          5. Radiotherapy with a wide field of radiation within 4 weeks of the first dose of study
             treatment.

          6. Clinically significant abnormalities of glucose metabolism as defined by any of the
             following:

               -  Diabetes mellitus Type I or Type II requiring insulin treatment.

               -  HbA1c ≥8.0% (63.9 mmol/mol).

          7. Spinal cord compression or brain metastases unless asymptomatic, treated and stable
             and not requiring steroids for at least 4 weeks prior to start of study treatment.

          8. Past medical history of interstitial lung disease, drug-induced interstitial lung
             disease, radiation pneumonitis which required steroid treatment, or any evidence of
             clinically active interstitial lung disease.

          9. As judged by the investigator, any evidence of severe or uncontrolled systemic
             diseases, including uncontrolled hypertension, active bleeding diatheses, or active
             infection including hepatitis B, hepatitis C, and human immunodeficiency virus.
             Screening for chronic conditions is not required.

         10. Any of the following cardiac criteria:

               -  Mean resting corrected QT interval (QTc) >470 milliseconds obtained from 3
                  consecutive ECGs.

               -  Any clinically important abnormalities in rhythm, conduction, or morphology of a
                  resting ECG (eg, complete left bundle branch block, 3rd degree heart block).

               -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic
                  events such as heart failure, hypokalaemia, potential for torsades de pointes,
                  congenital long QT syndrome, family history of long QT syndrome or unexplained
                  sudden death under 40 years-of-age, or any concomitant medication known to
                  prolong the QT interval.

               -  Clinically significant heart disease as evidenced by myocardial infarction or
                  arterial thrombotic events in the past 6 months, severe or unstable angina, or
                  New York Heart Association NYHA Class II to IV heart failure or cardiac ejection
                  fraction measurement of <50%.

               -  Experience of any of the following procedures or conditions in the preceding 6
                  months: coronary artery bypass graft, angioplasty, vascular stent, myocardial
                  infarction, angina pectoris, congestive heart failure NYHA ≥2.

               -  Uncontrolled hypotension defined as - systolic BP <90 mmHg and/or diastolic BP<50
                  mmHg.

               -  Uncontrolled hypertension defined as - systolic BP >160 mmHg and/or diastolic BP
                  ≥95 mmHg.

               -  Cardiac ejection fraction outside institutional range of normal or <50%
                  (whichever is higher) as measured by echocardiogram (or multi gated acquisition
                  scan (MUGA), if an echocardiogram cannot be performed or is inconclusive).

         11. With the exception of alopecia, any unresolved toxicities from prior therapy greater
             than Common Terminology Criteria for Adverse Event (CTCAE) grade 1 at the time of
             starting study treatment.

         12. Absolute neutrophil count <1.5×10^9/L.

         13. Platelets <100×10^9/L.

         14. Haemoglobin <9 g/dL (<5.59 mmol/L). (Note: any blood transfusion must have been >14
             days prior to the determination of a haemoglobin ≥9 g/dL [≥5.59 mmol/L]).

         15. Aspartate aminotransferase (AST) >2.5 times the ULN if no demonstrable liver
             metastases or >5 times ULN in the presence of liver metastases. Total bilirubin >1.5
             times ULN (*patients with confirmed Gilbert's syndrome may be included in the study).
             Elevated alkaline phosphatase (ALP) is not exclusionary if due to the presence of bone
             metastasis and liver function is otherwise considered adequate in the investigator's
             judgement.

         16. Creatinine >1.5 times ULN concurrent with creatinine clearance <50 mL/min (measured or
             calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is
             only required when creatinine is >1.5 times ULN.

         17. Refractory nausea and vomiting, malabsorption syndrome, chronic gastrointestinal
             diseases, inability to swallow the formulated product or previous significant bowel
             resection that would preclude adequate absorption of capivasertib.

         18. Any other disease, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding that, in the investigator's opinion, gives reasonable suspicion of
             a disease or condition that contraindicates the use of an investigational drug, may
             affect the interpretation of the results, render the patient at high risk from
             treatment complications or interferes with obtaining informed consent.

         19. History of hypersensitivity to active or inactive excipients of capivasertib or drugs
             with a similar chemical structure or class to capivasertib.

         20. Judgement by the investigator that the patient should not participate in the study if
             the patient is unlikely to comply with study procedures, restrictions, and
             requirements.

         21. Evidence of dementia, altered mental status or any psychiatric condition that would
             prohibit understanding or rendering of informed consent.

         22. Previous allogeneic bone marrow transplant or solid organ transplant.

         23. Known immunodeficiency syndrome.

         24. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
             staff and/or staff at the study site).

         25. Abiraterone-specific exclusion criteria: Any restriction or contraindication based on
             the currently applicable approved abiraterone label that would prohibit the use of
             abiraterone.

         26. Enzalutamide-specific exclusion criteria: Any restriction or contraindication based on
             the currently applicable approved enzalutamide label that would prohibit the use of
             enzalutamide.
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of patients with dose limiting toxicity (DLT) for Part A1
Time Frame:Day 1 to day 56 for Part A1
Safety Issue:
Description:A DLT is defined as an AE that occurs from the first dose of study treatment up to and including the last day of the DLT period (day 1 to day 56 for Part A1) that is assessed as unrelated to the disease, intercurrent illness, or concomitant medications and that, despite optimal therapeutic interventions, meets any of the criteria defined in the protocol.

Secondary Outcome Measures

Measure:Area under curve (AUC) for capivasertib to characterize pharmacokinetics (PK) for each treatment combination
Time Frame:For capivasertib and enzalutamide combination, full sampling on day 25 and on day 53; for capivasertib and abiraterone combination, full sampling on day 25.
Safety Issue:
Description:To characterise the PK of capivasertib when given in combination with novel agents.
Measure:Maximum plasma concentration (Cmax) for capivasertib to characterize PK for each treatment combination
Time Frame:For capivasertib and enzalutamide combination, full sampling on day 25 and on day 53; for capivasertib and abiraterone combination, full sampling on day 25.
Safety Issue:
Description:To characterise the PK of capivasertib when given in combination with novel agents.
Measure:Soft tissue objective response rate (ORR) and radiological ORR for efficacy analyses of capivasertib for each treatment combination
Time Frame:From screening (-28 Day) to every 8 weeks after cycle 1 day 1 for the first 24 weeks and every 12 weeks thereafter up to 1.5 years for each treatment combination
Safety Issue:
Description:To determine the preliminary signs of activity of capivasertib in combination with novel agents in this patient population.
Measure:Duration of response (DoR) for efficacy analyses of capivasertib for each treatment combination
Time Frame:From screening (-28 Day) to every 8 weeks after cycle 1 day 1 for the first 24 weeks and every 12 weeks thereafter up to 1.5 years for each treatment combination
Safety Issue:
Description:To determine the preliminary signs of activity of capivasertib in combination with novel agents in this patient population.
Measure:Percentage change in tumour size for efficacy analyses of capivasertib for each treatment combination
Time Frame:From screening (-28 Day) to every 8 weeks after cycle 1 day 1 for the first 24 weeks and every 12 weeks thereafter up to 1.5 years for each treatment combination
Safety Issue:
Description:To determine the preliminary signs of activity of capivasertib in combination with novel agents in this patient population.
Measure:Radiographic progression free survival (rPFS) for efficacy analyses of capivasertib for each treatment combination
Time Frame:From screening (-28 Day) to every 8 weeks after cycle 1 day 1 for the first 24 weeks and every 12 weeks thereafter up to 1.5 years for each treatment combination
Safety Issue:
Description:To determine the preliminary signs of activity of capivasertib in combination with novel agents in this patient population.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • Metastatic
  • Castration Resistant
  • Prostate Cancer

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