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JOURNAL ONKOLOGIE – STUDIE
AARDVARC

A Study of AZD4635 With Durvalumab and With Cabazitaxel and Durvalumab in Patients With mCRPC.

Rekrutierend

NCT-Nummer:
NCT04495179

Studienbeginn:
August 2020

Letztes Update:
10.06.2021

Wirkstoff:
AZD4635, Durvalumab, Cabazitaxel

Indikation (Clinical Trials):
Prostatic Neoplasms

Geschlecht:
Männer

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
AstraZeneca

Collaborator:
Parexel

Studienleiter

Christopher J Sweeney, MBBS
Principal Investigator
Dana-Farber Cancer Institute

Kontakt

AstraZeneca Clinical Study Information Center
Kontakt:
Phone: 1-877-240-9479
E-Mail: information.center@astrazeneca.com
» Kontaktdaten anzeigen

Studienlocations
(3 von 43)

Research Site
10117 Berlin
(Berlin)
GermanyNoch nicht rekrutierend» Google-Maps
Research Site
01307 Dresden
(Sachsen)
GermanyNoch nicht rekrutierend» Google-Maps
Research Site
20246 Hamburg
(Hamburg)
GermanyNoch nicht rekrutierend» Google-Maps
Research Site
50937 Köln
(Nordrhein-Westfalen)
GermanyNoch nicht rekrutierend» Google-Maps
Research Site
68167 Mannheim
(Baden-Württemberg)
GermanyNoch nicht rekrutierend» Google-Maps
Research Site
48149 Muenster
(Nordrhein-Westfalen)
GermanyNoch nicht rekrutierend» Google-Maps
Research Site
72076 Tuebingen
(Baden-Württemberg)
GermanyNoch nicht rekrutierend» Google-Maps
Research Site
85259 Scottsdale
United StatesNoch nicht rekrutierend» Google-Maps
Research Site
10016 New York
United StatesNoch nicht rekrutierend» Google-Maps
Research Site
13620 Seongnam-si
Korea, Republic ofRekrutierend» Google-Maps
Research Site
G12 0YN Glasgow
United KingdomNoch nicht rekrutierend» Google-Maps
Research Site
NG7 2UH Nottingham
United KingdomNoch nicht rekrutierend» Google-Maps
Research Site
SM2 5PT Sutton
United KingdomNoch nicht rekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Detailed Description:

This is a Phase II, international, open-label, two-arm, non-randomised study of AZD4635 in

participants with mCRPC. Participants in each arm will be stratified by the presence of

measurable soft tissue metastasis (per Response Evaluation Criteria in Solid Tumours [RECIST

v1.1]) or bone-only metastasis (per Prostate Cancer Working Group 3 [PCWG3 criteria]). There

will be no formal comparisons between treatment arms.

AZD4635 plus durvalumab (Arm A) will consist of 80 participants with mCRPC previously treated

with one or more approved new hormonal agent(s) (NHAs) and one or more taxanes or

participants who are taxane ineligible.

AZD4635 plus durvalumab plus cabazitaxel (Arm B) will consist of 80 participants mCRPC

previously treated with docetaxel and one prior NHA.

As of November 2020, the Sponsor stopped enrolment in Arm A following decisions at the

program level, not related to any safety issues. Ongoing participants in Arm A may continue

treatment as planned.

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Histologically confirmed adenocarcinoma of the prostate.

2. Known castrate-resistant disease.

3. Evidence of disease progression ≤6 months.

4. Body weight >30 kg at screening.

5. Willingness to adhere to the study treatment-specific contraception requirements.

6. Adequate bone marrow reserve and organ function.

7. Adequate organ function for Arm A as demonstrated by all of the following laboratory

values:

- Alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) if no

demonstrable liver metastases or ≤5 × ULN in the presence of liver metastases.

- Aspartate aminotransferase (AST) ≤2.5 × ULN if no demonstrable liver metastases

or ≤5 × ULN in the presence of liver metastases

- Total bilirubin (TBL) ≤1.5 × ULN

- TBL ≤2.0 × ULN in the case of known Gilbert syndrome with normal direct bilirubin

8. Participants in Arm A must have received the following prior therapy:

- Maximum of 3 lines of therapy in the mCRPC setting

- Prior therapy with one or more NHAs (eg, abiraterone acetate, enzalutamide,

apalutamide, darolutamide) in either hormone-sensitive or hormone-refractory

settings

- Prior therapy with one or more lines of taxanes (eg, docetaxel and/or

cabazitaxel)

- Alternatively, must be taxane-ineligible

- Prior therapy can be in either the hormone-sensitive or the hormone-refractory

setting

9. Adequate organ function for Arm B as demonstrated by all of the following laboratory

values:

- AST and/or ALT ≤1.5 × ULN

- TBL ≤ ULN

- TBL ≤2.0 × ULN in the case of known Gilbert syndrome with normal direct bilirubin

10. Participants in Arm B must have received the following prior therapy:

- Prior docetaxel (taxane) in either hormone-sensitive or hormone-refractory

settings

- Received no prior cytotoxic chemotherapy other than docetaxel for prostate cancer

except for estramustine and except adjuvant/neo-adjuvant treatment completed >3

years ago.

- Prior therapy with only one NHAs (eg, abiraterone acetate or enzalutamide; prior

apalutamide is not permitted) for treatment of mCRPC in either hormone-sensitive

or hormone-refractory settings.

- Be suitable to receive concomitant Granulocyte-colony stimulating factor during

all cycles of cabazitaxel.

- Participants who meet inclusion criteria for Arm B will be allocated

preferentially to that arm until recruitment to that arm is completed.

Exclusion Criteria:

1. Active brain metastases or leptomeningeal metastases.

2. There must be no requirement for immunosuppressive doses of systemic corticosteroids

for at least 2 weeks prior to study enrollment.

3. History of pneumonitis requiring corticosteroids, second malignancy that is

progressing and/or received active treatment ≤3 years before the first dose of study

intervention, and hypersensitivity to polysorbate-80 if allocated to cabazitaxel.

4. As judged by the Investigator, any evidence of severe or uncontrolled systemic

diseases.

5. Creatinine clearance <40 mL/min (calculated by Cockcroft-Gault equation).

6. Prior exposure to immune-mediated therapy including.

7. Ongoing treatment with warfarin (Coumadin).

8. Major surgery (excluding placement of vascular access) within 4 weeks of the first

dose of study intervention.

Studien-Rationale

Primary outcome:

1. rPFS in each arm separately to determine the efficacy of AZD4635 plus durvalumab and of AZD4635 plus durvalumab plus cabazitaxel in participants with mCRPC (Time Frame - From first dose to first documented progression or death from any cause (whichever comes first). This is expected to be an average of 5.5 months for Arm A and 11 months for Arm B):
rPFS is defined as the time from first dose to radiographic progression, assessed by the Investigator per RECIST 1.1 (soft tissue) and PCWG3 criteria (bone) or death from any cause, whichever occurs first.



Secondary outcome:

1. rPFS by adenosine (ADO) signalling gene expression in high and low subgroups to determine the efficacy of AZD4635 plus durvalumab plus cabazitaxel in participants with mCRPC (Time Frame - From first dose to first documented progression or death from any cause (whichever comes first). This is expected to be an average of 11 months for Arm B):
rPFS is defined as the time from first dose to radiographic progression, assessed by the Investigator per RECIST 1.1 (soft tissue) and PCWG3 criteria (bone) or death from any cause, whichever occurs first.

2. Overall survival (OS) in each arm separately to determine the efficacy of AZD4635 plus durvalumab and of AZD4635 plus durvalumab plus cabazitaxel in participants with mCRPC (Time Frame - Arm A and B: Every 90 days from the last dose of study drug upto 2.2 years (expected)):
OS is defined as the time from first dose until death due to any cause regardless of whether the participant withdraws from study treatment or receives another anti-cancer therapy.

3. Objective response rate (ORR) in each arm separately to determine the efficacy of AZD4635 plus durvalumab and of AZD4635 plus durvalumab plus cabazitaxel in participants with mCRPC (Time Frame - From first dose to first documented progression or death from any cause (whichever comes first). This is expected to be an average of 5.5 months for Arm A and 11 months for Arm B):
Confirmed ORR is defined as the proportion of participants with a confirmed complete response (CR) or partial response (PR) using overall radiographic response assessed by RECIST v1.1 and PCWG-3 criteria (bone), and will be based on a subset of all treated participants with measurable disease at baseline per the site Investigator.

4. Duration of response (DoR) in each arm separately to determine the efficacy of AZD4635 plus durvalumab and of AZD4635 plus durvalumab plus cabazitaxel in participants with mCRPC (Time Frame - From first dose to first documented progression or death from any cause (whichever comes first). This is expected to be an average of 5.5 months for Arm A and 11 months for Arm B):
DoR is defined as the date of first documented response (which is subsequently confirmed) until the date of documented progression or death in the absence of disease progression.

5. Prostate-specific antigen (PSA50) response in each arm separately to determine the efficacy of AZD4635 plus durvalumab and of AZD4635 plus durvalumab plus cabazitaxel in participants with mCRPC (Time Frame - Arm A: Screening, Day 1 of each cycle upto 11 months (expected). Duration of each cycle is 28 days; Arm B: Screening, Day 1 of each cycle upto 11 months (expected); Duration of each cycle is 28 days):
Confirmed PSA50 response is defined as the proportion of participants achieving a ≥50% decrease in PSA from baseline to the lowest post-baseline PSA, confirmed by a consecutive PSA at least 3 weeks later and will be based on PSA evaluable participants (dosed participants with an abnormal baseline PSA [≥1 ng/mL]).

6. Change from baseline in worst pain, average pain and pain interference in the daily activities scales of the Brief Pain Inventory - Short Form (BPI-SF) (Time Frame - Arm A: Screening, Day 1 of each cycle upto 12 months (expected). Duration of each cycle is 28 days; Arm B: Screening, Day 1 of each cycle upto 12 months (expected); Duration of each cycle is 28 days):
Worst pain, average pain and pain's interference with daily life will be assessed during the study intervention using the BPI-SF. The BPI-SF comprises a total of 15 items measuring 2 domains: pain severity and pain interference. Items measuring pain severity (including 'worst pain') are rated on an 11-point numeric rating scale (NRS)[ ranging from 0=No pain to 10=Pain as bad as you can imagine.

7. Time to pain progression based on BPI-SF Item 3 "pain at its worst in the last 24 hours" (Time Frame - Arm A: Screening, Day 1 of each cycle upto 12 months (expected). Duration of each cycle is 28 days; Arm B: Screening, Day 1 of each cycle upto 12 months (expected); Duration of each cycle is 28 days):
Pain progression will be assessed using BPI-SF.

8. Change from baseline in the FACT Advanced Prostate Symptom Indext-6 (FAPSI-6), as derived from 6 items, the FAPSI-8 from 8 items within the FACT-P and the Prostate Cancer Symptoms (PCS), from the 12 items in the prostrate-specific module of the FACT-P (Time Frame - Arm A: Screening, Day 1 of each cycle upto 12 months (expected). Duration of each cycle is 28 days; Arm B: Screening, Day 1 of each cycle upto 12 months (expected); Duration of each cycle is 28 days):
The Functional Assessment of Cancer Therapy-Prostate (FACT-P) will be used to measure health related quality of life (HRQL)in men with prostate cancer. It consists of 4 subscales (physical, emotional, functional and social/family well-being) plus a 12-item prostate-specific module, the PCS subscale, which highlights concerns specific to participants with prostate cancer.

9. Pharmacokinetic (PK) plasma concentrations for AZD4635, durvalumab and cabazitaxel (Time Frame - Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 14 months (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 14 months (expected); Cycle duration for Arm A is 28 days and Arm B is 21 days):
Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.

10. Maximum observed plasma concentration (Cmax) (Time Frame - Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 14 months (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 14 months (expected); Cycle duration for Arm A is 28 days and Arm B is 21 days):
Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.

11. Time to reach Cmax (Time Frame - Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 14 months (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 14 months (expected); Cycle duration for Arm A is 28 days and Arm B is 21 days):
Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.

12. Time of the last measurable concentration (tlast) (Time Frame - Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 14 months (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 14 months (expected); Cycle duration for Arm A is 28 days and Arm B is 21 days):
Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.

13. Terminal elimination rate constant (λz) (Time Frame - Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 14 months (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 14 months (expected); Cycle duration for Arm A is 28 days and Arm B is 21 days):
Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.

14. Terminal half-life (t1/2λz) (Time Frame - Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 14 months (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 14 months (expected); Cycle duration for Arm A is 28 days and Arm B is 21 days):
Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.

15. Area under the plasma concentration time curve from zero to 24 hours [AUC(0-24)], from zero to 8 hours [AUC(0-8)], from zero to the time of the last measurable concentration (AUClast), and from zero extrapolated to infinity (AUCinf) (Time Frame - Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 14 months (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 14 months (expected); Cycle duration for Arm A is 28 days and Arm B is 21 days):
Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.

16. Apparent plasma clearance (CL/F for AZD4635, CL/F for cabazitaxel) (Time Frame - Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 14 months (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 14 months (expected); Cycle duration for Arm A is 28 days and Arm B is 21 days):
Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.

17. Apparent volume of distribution during the terminal phase (Vz/F for AZD4635, Vz/F for cabazitaxel) (Time Frame - Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 14 months (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 14 months (expected); Cycle duration for Arm A is 28 days and Arm B is 21 days):
Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.

18. Mean residence time (MRT) (Time Frame - Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 14 months (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 14 months (expected); Cycle duration for Arm A is 28 days and Arm B is 21 days):
Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.

19. Number of subjects with serious and non-serious adverse events (Time Frame - Arm A: From Screening upto 14 months (expected); Arm B: From Screening upto 14 months (expected)):
To assess safety and tolerability of each treatment regimen in participants with mCRPC.

Studien-Arme

  • Experimental: Arm A: AZD4635 + durvalumab
    AZD4635 plus durvalumab (Arm A) will consist of participants with mCRPC previously treated with one or more approved NHAs (eg, abiraterone acetate, enzalutamide, apalutamide and/or darolutamide), and one or more taxanes, or participants who are taxane ineligible.
  • Experimental: Arm B: AZD4635 + durvalumab + cabazitaxel
    AZD4635 plus durvalumab plus cabazitaxel (Arm B) will consist of participants with mCRPC previously treated with docetaxel and one prior NHA (either abiraterone acetate or enzalutamide but not both (prior apalutamide is not allowed in Arm B).

Geprüfte Regime

  • AZD4635:
    Subjects will receive AZD4635 orally daily
  • Durvalumab:
    Subjects will receive intravenous durvalumab every 4 weeks for Arm A and every 3 weeks for Arm B.
  • Cabazitaxel:
    Subjects will receive intravenous cabazitaxel every 3 weeks

Quelle: ClinicalTrials.gov


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