An Open-label, Phase II Study of AZD4635 in Patients With Prostate Cancer

NCT04089553 | Completed Phase 2 Results FDA Drug

• 3 other identifiers: D8731C00001GU 156264471
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 9

Brief Summary

This is an open-label Phase II modular study in participants with prostate cancer which will assess safety, efficacy, and tolerability of AZD4635 in combination with other therapeutic agents in different treatment arms (referred to as modules). Combinations to be studied include: 1) Module 1: AZD4635 plus durvalumab; 2) Module 2: AZD4635 plus oleclumab.

Conditions

Prostate Cancer; Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Keywords

Prostate cancer; AZD4635; oleclumab; durvalumab; MEDI9447; Adenosine 2A Receptor Antagonist; A2AR

Outcome Measures

Primary Outcomes (2)

• Percentage of Participants With Confirmed Objective Response Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

  The confirmed objective response is defined as confirmed complete response (CR) or confirmed partial response (PR) based on RECIST v1.1 guidelines, assessed by computed tomography (CT) scan/ magnetic resonance imaging (MRI) scan/ positron emission tomography (PET) scan and bone scan. The CR is defined as disappearance of all target and non-target lesions and no new lesions. The PR is defined as \>= 30% decrease in the sum of the diameters of target lesions compared to baseline and no new non-target lesion. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression in-between.

  Baseline (Day -28) through end of study (last participant last visit) (approximately 22 months)

• Percentage of Participants With Confirmed Prostate-specific Antigen (PSA) Response Per Prostate Cancer Working Group 3 (PCWG3) Criteria

  A confirmed PSA response is defined as reduction in the PSA level of \>= 50% from baseline to the lowest post-baseline PSA results, measured twice, at least 3 weeks apart by the PCWG3 criteria.

  Baseline (Day -28) through end of study (last participant last visit) (approximately 22 months)

Secondary Outcomes (11)

• Percentage of Participants With Radiological Progression Free Survival (rPFS) at 6 Months

  Baseline (Day -28) through end of study (last participant last visit) (approximately 22 months)

• Duration of Response (DoR)

  Baseline (Day -28) through end of study (last participant last visit) (approximately 22 months)

• Overall Survival (OS)

  Baseline (Day -28) through end of study (last participant last visit) (approximately 22 months)

• Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab

  Pre-dose on Day 1 of Cycles 1, 2, 4, and 7 and 90 days following the last dose of durvalumab (approximately 22 months)

• Number of Participants With Positive ADA to Oleclumab

  Pre-dose on Day 1 of Cycles 1, 3, 5, and every 12 weeks thereafter, and 90 days following the last dose of oleclumab (approximately 22 months)

Study Arms (2)

Module 1 (AZD4635 75 mg + Durvalumab 1500 mg)

EXPERIMENTAL

Participants will receive monotherapy of AZD4635 75 mg orally once daily (QD) for first 14 days and thereafter will continue to receive 75 mg orally QD in combination with durvalumab 1500 mg intravenously (IV) every 4 weeks (Q4W) until will derive clinical benefit as judged by the investigator, confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first.

Drug: AZD4635; Drug: Durvalumab

Module 2 (AZD4635 50 / 75 mg + Oleclumab 1500 mg)

EXPERIMENTAL

Participants will receive combination therapy of AZD4635 (50 mg / 75 mg orally QD) and oleclumab 1500 mg IV (every 2 weeks of 28-day cycle for the first 4 doses and Q4W thereafter) until will derive clinical benefit as judged by the investigator or until confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first.

Drug: AZD4635; Drug: Oleclumab

Interventions

AZD4635 DRUG

In Module 1, participants will receive AZD4635 75 mg capsule orally QD for first 14 days and thereafter will continue to receive 75 mg orally QD Q4W. In Module 2, participants will receive AZD4635 50 mg / 75 mg capsule orally QD Q2W of 28-day cycle for the first 4 doses and Q4W thereafter. In both modules, participants will receive treatment until will derive clinical benefit as judged by the investigator or until confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first.

Module 1 (AZD4635 75 mg + Durvalumab 1500 mg); Module 2 (AZD4635 50 / 75 mg + Oleclumab 1500 mg)

Oleclumab DRUG

In Module 2, participants will receive oleclumab 1500 mg IV (solution for infusion after dilution, 50 mg/mL) Q2W of 28-day cycle for the first 4 doses and Q4W thereafter until will derive clinical benefit as judged by the investigator or until confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first.

Also known as: MEDI9447

Module 2 (AZD4635 50 / 75 mg + Oleclumab 1500 mg)

Durvalumab DRUG

In Module 1 after monotherapy of AZD4635, participants will receive durvalumab 1500 mg IV (solution for infusion after dilution, 50 mg/mL) Q4W until will derive clinical benefit as judged by the investigator or until confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first.

Also known as: Imfinzi, MEDI4736

Module 1 (AZD4635 75 mg + Durvalumab 1500 mg)

Eligibility Criteria

• Age: 18 Years - 130 Years
• Gender Eligibility Details: This study will enroll only male participants because the condition being studied is metastatic castration-resistant prostate cancer.
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses
• Participant must be ≥18 years of age at the time of signing the inform consent form (ICF)
• Participants must have prostate cancer with histological or cytological confirmation
• Participants must have previously received and progressed on standard-of-care therapy(ies)
• Participants must be able to provide an archival tumor tissue sample. If archival tumor tissue is not available, then tissue from a fresh tumor biopsy is required.
• All participants will be required to have a site of disease that is safely accessible for biopsy (paired) upon enrollment unless there are sufficient paired samples for the analysis. Accessible lesions are defined as those which are biopsiable (at screening) and amenable to repeat biopsy (after 2 weeks of AZD4635 therapy), unless clinically contraindicated. The provision of paired biopsies will be closely monitored to ensure the desired number of biopsiable participants are enrolled and investigators are aware of this requirement at all times.
• Participants with measurable disease must have at least 1 documented lesion on either a bone scan or a computed tomography (CT)/ magnetic resonance imaging (MRI) scan that can be followed for response and is suitable for repeated measurement, or participants with non-measurable disease must have measurable PSA ≥1.0 ng/mL if the confirmed rise is the only indication of progression (excluding small cell carcinoma) 8 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no clinical deterioration over the previous 2 weeks prior to the 28-day screening period and likely able to complete at least 12 weeks of treatment.
• \. Ability to swallow and retain oral medication. 10. Must have life expectancy of at least 12 weeks 11. Body weight ≥ 35 kg at screening 12. Willingness to adhere to the study treatment-specific contraception requirements: Participants must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) for the duration of the study (from the time they sign ICF) and for 3 months after the last dose of AZD4635 to prevent pregnancy in a female partner. Male participants must not donate or bank sperm for 24 weeks after treatment.
• Participants must have metastatic castrate resistant prostate cancer with histological or cytological confirmation. Participant may have bone-only metastatic disease.
• Participants must have had either orchiectomy or be on luteinizing hormone-releasing hormone (LHRH) agonist or antagonist therapy with testosterone \<50 ng/dL and agree to stay on LHRH agonist or antagonist therapy during the study
• Participants must have previously received and progressed on ≥2 lines of approved systemic therapy for metastatic castration-resistant prostate cancer (mCRPC), including a second generation hormonal agent (e.g, abiraterone, enzalutamide, or apalutamide)
• Participants must have evidence of mCRPC that progressed within 6 months prior to screening according to one of the following:
• PSA progression as defined by a minimum of 2 rising PSA levels with an interval of ≥1 week between each assessment, where the PSA value at screening should be ≥ 1.0 ng/mL.
• Radiographic disease progression in soft tissue based on RECIST Version 1.1 criteria with or without PSA progression.
• Radiographic disease progression in bone defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression.

You may not qualify if:

• History or presence of another primary invasive malignancy except for: malignancy treated with curative intent and with no known active disease ≥2 years before the first dose of study drug and of low potential risk for recurrence; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; adequately treated carcinoma in situ without evidence of disease; localized non-invasive primary carcinoma under surveillance
• Refractory nausea and vomiting, chronic gastrointestinal diseases, or previous significant small bowel resection that would preclude adequate absorption of AZD4635.
• Previously untreated brain metastases. Participants who have received radiation or surgery for brain metastases are eligible if therapy was completed at least 21 days previously and there is no evidence of central nervous system (CNS) disease progression or mild neurologic symptoms.
• With the exception of alopecia, lymphopenia, and hypothyroidism, any unresolved toxicities from prior therapy greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0) Grade 1 at the time of starting study treatment
• Participants with prior ≥ Grade 3, serious, or life threatening immune-mediated reactions following prior anti-PD-1, anti-PD-L1, or other immuno-oncology therapies.
• Prior history of myocardial infarction, transient ischemic attack, or stroke in the last 3 months
• Participants must have normotensive or well controlled blood pressure (\<150/90), with or without current antihypertensive treatment. If there is a diagnosis or history of hypertension, participant must have adequately controlled blood pressure on antihypertensive medications, as demonstrated by 2 blood pressure measurements taken in the clinical setting by a medical professional within 1 week prior to enrollment. Patients on a hypertensive medication must be willing and able to measure and record blood pressure readings twice-daily for a minimum of 3 weeks.
• As judged by the Investigator or Medical Monitor, any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, or active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B virus \[known positive HBV surface antigen (HBsAg) result\], hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies), or active hepatitis A. Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Participants positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Screening for chronic conditions is not required.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis, Crohn's disease\], diverticulitis, celiac disease, systemic lupus erythematous, Wegener's syndrome, myasthenia gravis, Grave's disease, rheumatoid arthritis, hypophysitis, uveitis, autoimmune pneumonitis, autoimmune nephritis or nephropathy, etc.) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion: a) vitiligo or alopecia, b) hypothyroidism (e.g., following Hashimoto's disease) stable on hormone replacement, c) psoriasis or eczema not requiring systemic therapy for disease control, d) celiac disease controlled by diet alone.
• Prior/concomitant therapy with AZD4635 or any other A2AR antagonist.
• Ongoing corticosteroid use, at doses above physiologic replacement therapy. The following are exceptions to this criterion: a) use of intranasal, inhaled, topical orticosteroids, local steroid injections (e.g. intra-articular injections), b) steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication) are permitted, c) systemic corticosteroids at physiologic doses below 10 mg/day of prednisone or equivalent.
• The following intervals between the end of the prior treatment and first dose of study drug must be observed: a) anticancer therapy: ≥21 days or 5 half-lives (whichever is shorter) of the first dose of study drug. At least 7 days must have elapsed between the last dose of such agent and the first dose of study drug. (Exception: androgen-deprivation therapy is required to maintain castrate levels of testosterone (˂50 ng/dL), b) concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.
• Major surgery (as defined by the Medical Monitor, excluding placement of vascular access) within 4 weeks of the first dose of study treatment.
• Minor surgical procedures (as defined by the Medical Monitor) within 7 days of the first dose of study treatment.
• Participant is receiving medications or other products known to be sensitive breast cancer resistance protein (BCRP) or organic anion transporter polypeptide 1 (OATP1B1), OATP1B3, organic anionic transporter 1 (OAT1), organic cation transporter 1 (OCT1), OCT2, multidrug and toxin extrusion protein 1 (MATE1) and P glycoprotein (P-gp) substrates or potent or moderate inhibitors/inducers of CYP1A2, which cannot be discontinued 2 weeks prior to Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of AZD4635.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (9)

Research Site

Denver, Colorado, 80218, United States

Location

Research Site

Fort Myers, Florida, 33916, United States

Location

Research Site

St. Petersburg, Florida, 33705, United States

Location

Research Site

West Palm Beach, Florida, 33401, United States

Location

Research Site

Decatur, Illinois, 62526, United States

Location

Research Site

New York, New York, 10032, United States

Location

Research Site

Durham, North Carolina, 27710, United States

Location

Research Site

Chattanooga, Tennessee, 37404, United States

Location

Research Site

Nashville, Tennessee, 37203, United States

Location

Related Publications (1)

• Falchook GS, Reeves J, Gandhi S, Spigel DR, Arrowsmith E, George DJ, Karlix J, Pouliot G, Hattersley MM, Gangl ET, James GD, Thompson J, Russell DL, Patel B, Kumar R, Lim E. A phase 2 study of AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer. Cancer Immunol Immunother. 2024 Mar 2;73(4):72. doi: 10.1007/s00262-024-03640-6.

  PMID: 38430405 DERIVED

Related Links

• Redacted CSR Synopsis
• Related Info
• Related Info

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

durvalumab

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Results Point of Contact

• Title: Global Clinical Lead
• Organization: AstraZeneca Clinical Study Information Center

information.center@astrazeneca.com

1-877-240-9479

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 29, 2019
• First Posted: September 13, 2019
• Study Start: August 29, 2019
• Primary Completion: June 16, 2021
• Study Completion: April 11, 2023
• Last Updated: April 16, 2024
• Results First Posted: July 8, 2022

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

US (9)