Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04089553
Recruitment Status : Recruiting
First Posted : September 13, 2019
Last Update Posted : November 18, 2019
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:

This is an open-label Phase II modular study in patients 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.

The protocol may be amended to include other combinations.


Condition or disease Intervention/treatment Phase
Prostate Cancer Metastatic Castration-Resistant Prostate Cancer (mCRPC) Drug: AZD4635 Drug: Oleclumab Drug: Durvalumab Phase 2

Detailed Description:

This is an open-label Phase II modular study in patients with prostate cancer which will assess safety, efficacy, and tolerability of AZD4635 in combination with other therapeutic agents in different treatment arm (referred to as modules).

Combinations to be studied include: 1) Module 1: AZD4635 plus durvalumab; 2) Module 2: AZD4635 plus oleclumab. The protocol may be amended to include other combinations.

All patients will be allocated into a module using an Interactive Web Response System (IWRS). Randomization will occur when patients meet eligibility criteria for two or more modules that are currently recruiting. If patients only meet the criteria for only one currently recruiting module, they will be allocated to that module without randomization taking place.

The primary objective of the clinical study is to evaluate the efficacy of each combination therapy by: 1) assessing the objective response rate (ORR) of patients with measurable disease [response will be determined by Response Evaluation Criteria in Solid Tumours (RECIST 1.1)]; 2) assessing the PSA confirmed response rate of each combination therapy [PSA confirmed response rate is defined as the proportion of participants with a reduction in the PSA level of ≥50% measured from baseline to the lowest post-baseline PSA result measured twice, at least 3 weeks apart by the Prostate Cancer Working Group 3 criteria PCWG3).

The primary safety endpoints include assessment of adverse events and serious adverse events, physical examinations, vital signs, and collection of clinical chemistry/hematology parameters

In Modules 1 and 2 there will be approximately 30 evaluable patients in each module, and at least 20 patients will have RECIST measurable disease at baseline. If any of the required patients for PSA and/or ORR are not evaluable for PSA response or tumor response, respectively, they may be replaced at the sponsor's discretion.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Multi-drug, Multi-center Phase II Combination Study of AZD4635 in Patients With Prostate Cancer
Actual Study Start Date : August 29, 2019
Estimated Primary Completion Date : March 15, 2021
Estimated Study Completion Date : March 15, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer
Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: Module 1
Module 1 will investigate the safety, efficacy, and tolerability of AZD4635 in combination with durvalumab in post-standard of care therapy for metastatic castration resistant prostate cancer (mCRPC) patients. In Module 1 approximately 30 patients will be enrolled, and biopsies will be obtained from a minimum of 15 patients in order to assess tumor microenvironment at baseline and after treatment with AZD4635. Patients will receive AZD4635 75 mg PO QD monotherapy for 2 weeks (Cycle 0). Starting with Cycle 1, durvalumab 1500 mg IV Q4W will be added to continuous AZD4635 dosing.
Drug: AZD4635
Capsule

Drug: Durvalumab
Durvalumab will be supplied as a solution for infusion after dilution. After dilution the solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine HCl, 275 mM trehalose dihydrate, and 0.02%(w/v) polysorbate 80.
Other Name: Imfinzi

Experimental: Module 2

Module 2 will investigate the safety, efficacy, and tolerability of AZD4635 in combination with oleclumab in post-standard of care therapy for metastatic castration resistant prostate cancer (mCRPC) patients. In Module 2 approximately 30 patients will be enrolled, and biopsies will be obtained from a minimum of 15 patients in order to assess tumor microenvironment at baseline and after treatment with AZD4635 plus oleclumab.

Patients will receive a starting dose of AZD4635 50 mg PO QD and oleclumab 1500 mg Q2W for the first 4 doses and Q4W thereafter. Administration of the first dose of oleclumab must be staggered by a minimum of 24 hours between the first 6 patients. After the first 6 patients have completed 28 days of therapy with AZD4635 and oleclumab, there will be an early review for safety/toxicity by a Safety Review Committee (SRC) with stopping rules for toxicity.

Drug: AZD4635
Capsule

Drug: Oleclumab
Oleclumab is supplied as a solution for infusion after dilution. After dilution the solution contains 50 mg/mL oleclumab (MEDI9447) in 25 mM histidine/histidine HCl, 240 mM sucrose, 0.03% (w/v) polysorbate 80;
Other Name: MEDI9447




Primary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: Up to approximately 2 years ]
    ORR is defined as the proportion of patients with measurable disease at baseline who have a confirmed response as assessed by the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). Reassessment of tumors must be done by the same methods used to establish baseline tumor measurements.

  2. Prostate-specific antigen (PSA) Response [ Time Frame: Up to approximately 2 years ]
    PSA confirmed response is defined as the proportion of participants with a 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 Prostate Cancer Working Group 3 criteria (PCWG3).


Secondary Outcome Measures :
  1. Radiologic Progression Free Survival (PFS) at Six Months [ Time Frame: Six months ]
    The proportion of patients alive and radiologically progression free at 6 months using assessment methods described in RECIST 1.1 (soft tissue lesions) and PCWG3 (bone lesions).

  2. Duration of Response (DoR) [ Time Frame: Throughout the study (up to approximately 2 years) ]
    Duration of Response (DoR) is defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression.

  3. Overall Survival (OS) [ Time Frame: Throughout the study (up to approximately 2 years) ]
    Overall survival is defined as the length of time from date of first dose until the date of death due to any cause.

  4. Durvalumab Anti-Drug Antibodies (ADA) [ Time Frame: Anti-drug antibodies (ADAs) to durvalumab will be assessed pre-dose Day 1 of Cycles 1, 2, 4, 7 & 90 days after the last dose. Each cycle is 28 days. ]
    The proportion of patients with the presence of anti-drug antibody (ADA) will be determined.

  5. Oleclumab Anti-Drug Antibodies (ADA) [ Time Frame: Anti-drug antibodies (ADAs) to oleclumab will be assessed pre-dose on Day 1 of Cycles 0, 1, 3, 5 & every 12 weeks thereafter, & 90 days after the last dose. Each cycle is 28 days. ]
    The proportion of patients with the presence of anti-drug antibody (ADA) will be determined.

  6. Minimum steady state plasma concentration (Ctrough) of AZD4635. [ Time Frame: Day 1 of Cycles 1, 2, 4, and 7 and 90 days after last dose (up to approximately 260 days). Each cycle is 28 days. ]
    Pre-infusion and end of infusion plasma concentrations will be determined on Day 1 of Cycles 1 and 4. Only pre-infusion concentration will be determined on Day 1 of cycles 2 and 7.

  7. Proportion of Patients Experiencing Adverse Events [ Time Frame: Throughout the study (up to approximately 2 years) ]
    Safety and tolerability will be judged by assessment of the severity and proportion of patients experiencing adverse events (AEs) and serious adverse events (SAEs), assessment of abnormalities in physical exam findings, vital signs, clinical chemistry, hematology, and coagulation parameters, and urinalysis parameters.

  8. Proportion of Patients Experiencing Serious Adverse Events [ Time Frame: Throughout the study (up to approximately 2 years) ]
    Safety and tolerability will be judged by assessment of the severity and proportion of patients experiencing adverse events (AEs) and serious adverse events (SAEs), assessment of abnormalities in physical exam findings, vital signs, clinical chemistry, hematology, and coagulation parameters, and urinalysis parameters.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Gender Eligibility Description:   This study will enroll only male subjects because the condition being studied is metastatic castration-resistant prostate cancer.
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria for all Patients in all Modules.

Patients are eligible to be included in the study only if all of the following inclusion criteria are met and none of the exclusion criteria apply:

  1. Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses.
  2. Patient must be ≥18 years of age at the time of signing the ICF.
  3. Patients must have prostate cancer with histological or cytological confirmation.
  4. Patients must have previously received and progressed on standard-of-care therapy(ies).
  5. Patients 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.
  6. A minimum of 15 patients per module will be required to have a site of disease that is safely accessible for biopsy (paired) upon enrollment. 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 patients are enrolled and investigators are aware of this requirement at all times.
  7. Patients with measurable diseases 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 patients 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.

9. Ability to swallow and retain oral medication.

10. Body weight >35 kg at screening

11. Willingness to adhere to the study treatment-specific contraception requirements: Patients 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 patients must not donate or bank sperm for 24 weeks after treatment.

Inclusion Criteria for Module 1

  1. Patients must have had either orchiectomy or be on luteinizing hormone-releasing hormone (LHRH) agonist or antagonist therapy with serum testosterone <50 ng/dL, and agree to stay on LHRH agonist or antagonist therapy during the study.
  2. Patients must have previously received and progressed on >2 lines of approved systemic therapy for mCRPC, including a second generation hormonal agent (e.g., abiraterone, enzalutamide, or apalutamide).
  3. Patients must have evidence of mCRPC that progressed within 6 months prior to screening according to one of the following:

    1. 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.
    2. Radiographic disease progression in soft tissue based on RECIST Version 1.1 criteria with or without PSA progression.
    3. Radiographic disease progression in bone defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression.

Inclusion Criteria for Module 2.

  1. Patients must have had either orchiectomy or be on luteinizing hormone-releasing hormone (LHRH) agonist or antagonist therapy with serum testosterone <50 ng/dL, and agree to stay on LHRH agonist or antagonist therapy during the study.
  2. Patients must have previously received and progressed on >2 lines of approved systemic therapy for mCRPC, including a second generation hormonal agent (e.g., abiraterone, enzalutamide, or apalutamide).
  3. Patients must have evidence of mCRPC that progressed within 6 months prior to screening according to one of the following:

    1. 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.
    2. Radiographic disease progression in soft tissue based on RECIST Version 1.1 criteria with or without PSA progression
    3. Radiographic disease progression in bone defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression.

EXCLUSION CRITERIA

Exclusion Criteria for all Patients in all Modules

Patients must not enter the study if any of the following exclusion criteria apply:

  1. Refractory nausea and vomiting, chronic gastrointestinal diseases, or previous significant small bowel resection that would preclude adequate absorption of AZD4635.
  2. Previously untreated brain metastases. Patients 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 CNS disease progression or mild neurologic symptoms.
  3. With the exception of alopecia, lymphopenia, hypothyroidism, or 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.
  4. Patients with prior ≥ Grade 3, serious, or life threatening immune-mediated reactions following prior anti-PD-1, anti-PD-L1, or other immuno-oncology therapies.
  5. Patients must have normotensive or well controlled blood pressure (<140/90), with or without current antihypertensive treatment. If there is a diagnosis or history of hypertension, patient 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.
  6. 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.

    Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients 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.

  7. 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.
  8. Prior/concomitant therapy with AZD4635 or any other A2AR antagonist.
  9. 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.
  10. 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. (Exception: androgen-deprivation therapy is permitted), b) concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.
  11. Major surgery (as defined by the Medical Monitor, excluding placement of vascular access) within 4 weeks of the first dose of study treatment.
  12. Minor surgical procedures (as defined by the Medical Monitor) within 7 days of the first dose of study treatment.
  13. Patient is receiving medications or other products known to be sensitive breast cancer resistance protein (BCRP) or organic anion transporter 1 (OAT1) substrates or potent 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.
  14. Concomitant medications with another A1R antagonist that would increase risk of seizure (e.g., theophylline, aminophylline).
  15. Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment.
  16. Ongoing treatment with Coumadin.
  17. Receipt of live attenuated vaccine within 30 days prior to the first dose of study drug.
  18. Herbal preparations/medications are not allowed throughout the study, including bu not limited to: St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Patients should stop using these herbal medications 7 days prior to the first dose of AZD4635.
  19. Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks, of the first dose of study treatment.
  20. Enrollment into another therapeutic clinical trial. (Exception: Patients are allowed to participate in investigational imaging or non-interventional studies.)
  21. History of hypersensitivity to AZD4635 or drugs with a similar chemical structure or class to AZD4635.
  22. Any of the following cardiac criteria:

    • Mean resting corrected QT interval (QTcF) >470 msec obtained from 3 ECGs.
    • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block
    • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication with known or possible risk of QT interval prolongation.
    • Ejection fraction <55% or the lower limit of normal of the institutional standard.
  23. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

    • Absolute neutrophil count <1.5 x 10⁹/L
    • Platelet count <100 x 10⁹/L
    • Hemoglobin <9.0 g/dL
    • Alanine aminotransferase (ALT) >2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases
    • Aspartate aminotransferase (AST) >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases
    • Total bilirubin (TBL) >1.5 times ULN
    • 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.
  24. Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and its representatives and/or staff at the study site).
  25. Judgment by the Investigator or Medical Monitor that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
  26. Participation in another clinical interventional study or if patient has already received at least one dose of study drug in the present study.

Exclusion Criteria for Module 1

Patients must not enter Module 1 of the study if any of the following exclusion criteria apply.

  1. Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.
  2. History of active primary immunodeficiency.
  3. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice).

Exclusion Criteria for Module 2

  1. Prior receipt of any immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies and agents targeting CD73, CD39, or adenosine receptors, excluding therapeutic anticancer vaccines.
  2. Known history of allergy or reaction to any component of oleclumab formulation or history of anaphylaxis to any human gammaglobulin therapy.
  3. Known sensitivity to acetaminophen/paracetamol, diphenhydramine or equivalent antihistamine, and methylprednisolone or equivalent glucocorticoid.
  4. History of venous thrombosis within the past 3 months.
  5. Prior history of myocardial infarction, transient ischemic attack, or stroke in the last three months.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04089553


Contacts
Layout table for location contacts
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
Layout table for location information
United States, Colorado
Research Site Recruiting
Denver, Colorado, United States, 80218
United States, Florida
Research Site Recruiting
Fort Myers, Florida, United States, 33916
Research Site Recruiting
Saint Petersburg, Florida, United States, 33705
Research Site Withdrawn
Sarasota, Florida, United States, 34232
United States, Massachusetts
Research Site Not yet recruiting
Boston, Massachusetts, United States, 02215
United States, New York
Research Site Withdrawn
New York, New York, United States, 10032
United States, Tennessee
Research Site Recruiting
Chattanooga, Tennessee, United States, 37404
Research Site Recruiting
Nashville, Tennessee, United States, 37203
Sponsors and Collaborators
AstraZeneca
Investigators
Layout table for investigator information
Study Chair: Charles Drake, MD, PhD Columbia University Medical Center, Herbert Irving Pavilion, New York, NY

Layout table for additonal information
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04089553     History of Changes
Other Study ID Numbers: D8731C00001
GU 156 ( Other Identifier: Sarah Cannon Development Innovations, LLC )
First Posted: September 13, 2019    Key Record Dates
Last Update Posted: November 18, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Prostate cancer
AZD4635
oleclumab
durvalumab
MEDI9447
Adenosine 2A Receptor Antagonist
A2AR
Additional relevant MeSH terms:
Layout table for MeSH terms
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Durvalumab
Antibodies, Monoclonal
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs