Phase II Trial of AZD6738 Alone and in Combination With Olaparib

• ClinicalTrials.gov Identifier: NCT03682289
• Recruitment Status: Recruiting
• First Posted: September 24, 2018
• Last Update Posted: April 6, 2021
• Sponsor: Rahul Aggarwal
• Collaborator: AstraZeneca
• Information provided by (Responsible Party): Rahul Aggarwal, University of California, San Francisco

Study Description

Brief Summary:

This phase II trial studies how well ATR kinase inhibitor AZD6738 works alone or in combination with olaparib in treating participants with renal cell carcinoma, urothelial carcinoma, all pancreatic cancers, endometrial cancer, and other solid tumors excluding clear cell ovarian cancer that have spread to nearby tissue or lymph nodes or other parts of the body. ATR kinase inhibitor AZD6738 and olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not known if giving ATR kinase inhibitor AZD6738 with or without olaparib may work better in treating participants with solid tumors.

Condition or disease	Intervention/treatment	Phase
Clear Cell Renal Cell Carcinoma; Locally Advanced Pancreatic Cancer; Locally Advanced Malignant Solid Neoplasm; Metastatic Malignant Solid Neoplasm; Metastatic Renal Cell Carcinoma; Metastatic Urothelial Carcinoma; Metastatic Pancreatic Cancer; Stage III Pancreatic Cancer; Stage III Renal Cell Cancer; Stage IV Pancreatic Cancer; Stage IV Renal Cell Cancer	Drug: ATR Kinase Inhibitor AZD6738; Drug: Olaparib	Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To assess objective response rate (ORR) of ATR kinase inhibitor AZD6738 (AZD6738) monotherapy and AZD6738 + olaparib by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

SECONDARY OBJECTIVES:

I. To determine the median duration of response (DOR) in each study arm. II. To determine the median progression-free survival and progression-free survival rate at 6 and 12 months in each study arm.

III. To further characterize the safety and tolerability profile of AZD6738 alone and in combination with olaparib.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 68 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of AZD6738 Alone and in Combination With Olaparib in Patients With Selected Solid Tumor Malignancies
• Actual Study Start Date: January 17, 2019
• Estimated Primary Completion Date: December 31, 2023
• Estimated Study Completion Date: December 31, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I (ATR kinase inhibitor AZD6738); Participants who are BAF250a negative or ATM-Mutant receive ATR kinase inhibitor AZD6738 PO twice a day on days 1-14. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: ATR Kinase Inhibitor AZD6738; Given by mouth; Other Names: AZD-6738; AZD6738
Experimental: Arm II (ATR kinase inhibitor AZD6738, olaparib); Participants who are BAF250a positive receive ATR kinase inhibitor AZD6738 PO every day on days 1-7 and olaparib PO twice a day on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: ATR Kinase Inhibitor AZD6738; Given by mouth; Other Names: AZD-6738; AZD6738; Drug: Olaparib; Given by mouth; Other Names: AZD2281; KU-0059436; Lynparza; poly adenosine diphosphate-ribose polymerase (PARP) inhibitor AZD2281

Outcome Measures

Primary Outcome Measures :

1. Objective response rate (ORR) [ Time Frame: Up to 2.5 years ]
   ORR will be measured using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Will be based on one-sided exact binomial test comparison of the observed ORR in evaluable patients to the null-hypothesized value of 5%, using the 5% significance level.
2. Composite Prostate Cancer Patient Response Rate [ Time Frame: Up to 12 months ]
   In prostate cancer patients only: To determine the 50% decline in prostate-specific antigen (PSA50) response rate Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria or objective response by RECIST 1.1
3. Objective response rate (ORR) for other solid tumors [ Time Frame: Up to 2.5 years ]
   ORR for participants with other solid tumors will be measured using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Will be based on one-sided exact binomial test comparison of the observed ORR in evaluable patients to the null-hypothesized value of 5%, using the 5% significance level.

Secondary Outcome Measures :

1. Median duration of response (DOR) [ Time Frame: Up to 2.5 years ]
   Summarized using Kaplan-Meier estimates with associated 95% confidence limits.
2. Median progression-free survival (PFS) [ Time Frame: Up to 12 months ]
   Summarized using Kaplan-Meier estimates with associated 95% confidence limits at 6 and 12 months
3. Progression-free survival (PFS) rate over time [ Time Frame: Up to 12 months ]
   The PFS rate at 6 and 12 months endpoint will be summarized as a proportion with an exact binomial 95% confidence interval.
4. Number of treatment-related adverse events (AEs) [ Time Frame: Up to 30 days post treatment ]
   Safety analyses will be descriptive summaries of the number of adverse events per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
5. Prostate Cancer Patient Progression Free Survival [ Time Frame: Up to 12 months ]
   In prostate cancer patients only, to determine the radiographic progression-free survival by PCWG3 criteria
6. Prostate Cancer Patient Response Rate [ Time Frame: Up to 12 months ]
   In prostate cancer patients only: To determine the 50% decline in prostate-specific antigen (PSA50) response rate Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patients must provide written informed consent prior to performance of study-specific procedures or assessments.

2. ARID1A Subgroup (N = 39):

   1. Histologically confirmed locally advanced or metastatic solid tumor malignancy with progression on at least one prior systemic therapy, including one of the following tumor types:

      • Renal cell carcinoma with predominant clear cell histology (Cohort A)
      • Urothelial carcinoma (Cohort B)
      • All pancreatic cancers (Cohort C)
      • Other solid tumors excluding clear cell ovarian cancer and endometrial cancer (Cohort D)
      • Endometrial cancer (Cohort E)
   2. Formalin-fixed paraffin embedded tumor tissue evaluable for BAF250a expression by ARID1A immunohistochemistry. Primary or metastatic tumor tissue is permissible. Patients without evaluable archival tissue may undergo optional tumor biopsy during Screening if other eligibility criteria have been met
   3. Measurable disease by RECIST 1.1

3. ATM Loss Subgroup (N = 20):

   1. Histologically confirmed locally advanced or metastatic solid tumor malignancy with progression on at least one prior systemic therapy, including one of the following tumor types:

      • Metastatic castration resistant prostate cancer (N = 10).

        • Patients may have evaluable or measurable disease by RECIST 1.1 criteria.
        • Prior treatment with at least one androgen signaling inhibitor (e.g. abiraterone, enzalutamide, apalutamide, darolutamide).
        • Patients will be required to maintain castrate levels of testosterone during study treatment with use of Luteinizing hormone-releasing hormone (LHRH) analog (except for patients with history of bilateral orchiectomy).
        • Progression by PCWG3 criteria at study entry
      • All other solid tumor malignancies (N = 10). Patients are required to have measurable soft tissue disease by RECIST 1.1 criteria.
   2. Archival tumor tissue evaluable for ATM expression by immunohistochemistry (IHC)
   3. Evidence of ATM loss by either pathogenic ATM mutation in Clinical Laboratory Improvement Amendments (CLIA) (CLIA)-approved assay and/or loss of ATM expression by IHC (Ventana Ab). An interim analysis will be performed after 10 patients are enrolled. If less than 50% of tumors have absence of ATM expression by IHC, subsequent enrollment of the remaining 10 patients will be required to have evidence of both ATM mutation and loss of ATM expression (< 5% of tumor cells expressing ATM) using CLIA-certified IHC test (Ventana).
4. Evidence of clinical or radiographic progression prior to study entry (except metastatic castrate-resistant prostate cancer (mCRPC) cohort which requires progression by PCWG3 criteria)
5. Age ≥ 18 years at time of signing informed consent form
6. Resolution of all prior treatment-related toxicities to grade 1 severity or lower (except alopecia).
7. Patients must be at least 3 weeks or 5 half-lives (whichever is shorter) from last standard or experimental non-cytotoxic therapy prior to first dose of protocol therapy. Patients must be > 21 days from last dose of cytotoxic chemotherapy prior to C1D1. The minimum wash-out period for immunotherapy is 42 days prior to C1D1.
8. Radiation therapy must be completed > 7 days prior to course 1 day 1 (C1D1) or > 28 days prior to C1D1 for patients receiving radiation to more than 30% of bone marrow.

9. Adequate organ function as defined by:

   • Hemoglobin (Hgb) >= 10.0 g/dL in the absence of transfusion within 14 days prior to screening laboratory assessment.
   • Platelets (Plt) count > 100,000 x 10^9/L.
   • Absolute neutrophil count > 1.5 x 10^9/L.
   • Estimated glomerular filtration rate (GFR) >= 51 ml/min based on Cockcroft-Gault equation or 24 hour urine collection.
   • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN) (< 5x ULN in patients with known liver metastases).
   • Total bilirubin < 1.5 x ULN (direct bilirubin < 1.5 x ULN in patients with known Gilbert's disease or UGT1A1 homozygote).
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

11. The effects of AZD6738 and olaparib on the developing human fetus are unknown. For this reason and because ATR and PARP inhibitors as well as other therapeutic drugs used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use 2 highly effective forms of contraception prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

    1. Male patients who are sexually active must be willing to use barrier contraception for the duration of the study and for 1 week after the last study drug administration, with all sexual partners. Male patients must use a condom during treatment and for 6 months after the last dose of study drug(s) when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception for 6 months after the last dose of study drug(s) if they are of childbearing potential. True abstinence for either sex is an acceptable form of contraception and must be documented as such.

    2. Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to C1D1 treatment). Evidence of postmenopausal status or non-child bearing status must be documented. Postmenopausal is defined as:

       • Aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
       • Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation, radiation-induced oophorectomy with last menses > 1 year ago, chemotherapy-induced menopause with > 1 year interval since last menses

       • Amenorrhoeic for 12 months and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and plasma oestradiol levels in the postmenopausal range for the institution for women under 50.

         • Ability to understand a written informed consent document, and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.

Exclusion Criteria:

1. History of secondary malignancy requiring treatment within 1 year prior to screening, with the exception of carcinoma in situ of the cervix, non-melanoma skin carcinoma, low/intermediate risk localized prostate cancer (=< Gleason 7, =< T2N0M0, and prostate-specific antigen (PSA) =< 20 ng/mL at diagnosis) (not applicable for prostate cancer cohort), ductal carcinoma in situ, Stage I uterine cancer, and non-muscle invasive urothelial carcinoma
2. Patients receiving, or having received within 14 days of C1D1, corticosteroids at a dose > 10 mg/day of prednisone (or equivalent).
3. Patients with myelodysplastic syndrome or features suggestive of myelodysplastic syndrome.
4. Prior treatment with ATR inhibitor
5. Major surgical procedures < 28 days prior to C1D1. Patients must have recovered to grade =< 1 for any adverse events related to the surgical procedure.

6. Untreated central nervous system (CNS) metastases. Patients with previously treated central nervous system (CNS) metastases are eligible if:

   • No requirement for corticosteroids at study entry
   • Radiographically and clinically stable for at least 4 weeks prior to study entry
   • No evidence of intra-tumoral hemorrhage
   • No evidence of current or prior leptomeningeal disease.

7. Clinically significant gastrointestinal abnormalities that may increase the risk of decreased absorption of medications, including:

   • Inability to swallow oral medications
   • Active peptic ulcer disease
   • Known intra-luminal metastatic lesions
   • History of abdominal fistula or bowel perforation
   • History of bowel obstruction within 6 months prior to study entry
   • Known malabsorption syndrome
   • Significant resection of the small bowel.
8. Fridericia's QT correction formula (QTcF) > 470 ms (females) or > 450 ms (males) on screening electrocardiography (ECG), or immediate family history of congenital long QT syndrome or sudden cardiac death at age less than 40.

9. History of any one or more of the following cardiovascular conditions within the past 6 months:

   • Myocardial infarction
   • Unstable angina
   • Transient ischemic attack or cerebrovascular accident
   • Uncontrolled arrhythmia. Rate controlled atrial fibrillation/flutter is not an exclusion for the study.
   • Class III or IV congestive heart failure or documented left ventricle (LV) ejection fraction of < 50% (screening not required).
10. Uncontrolled hypertension as defined by systolic blood pressure > 160 mm Hg and/or diastolic blood pressure > 100 mm Hg. Adjustment of anti-hypertensive regimen and re-screening is permitted.
11. Relative hypotension with resting blood pressure of less than 90 mm Hg systolic and less than 60 mm Hg diastolic or symptomatic orthostatic hypotension.
12. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with patient's safety or adherence to study procedures including uncontrolled infection requiring parenteral antibiotics.

13. Concomitant use of strong cytochrome P450, family 3, subfamily A (CYP3A4) inhibitors, strong CYP3A4 inducers, CYP3A4 substrates with narrow therapeutic index, or CYP2B6 substrates with narrow therapeutic index within 21 days or 5 half-lives, whichever is shorter, prior to C1D1 of study treatment

    • The use of herbal supplements or 'folk remedies' (and medications and foods that significantly modulate CYP3A activity) should be discouraged. If deemed necessary, such products may be administered with caution and the reason for use documented in the case report form (CRF).
14. A known hypersensitivity to olaparib, AZD6738 or any excipient of the product or any contraindication to the combination anti-cancer agent as per local prescribing information.
15. A known chronic active hepatitis B or C (defined by positive viral load; screening not required).
16. Immunocompromised patients, including those serologically positive for human immunodeficiency virus (HIV), those receiving chronic immunosuppression, or those with prior allogeneic or cord blood transplantation.

Contacts and Locations

Contacts

Contact: Erika Zigman; 877-837-3222; cancertrials@ucsf.edu

Locations

United States, California

University of California, San Francisco; Recruiting

San Francisco, California, United States, 94115

Contact: Erika Zigmam 877-837-3222 cancertrials@ucsf.edu

Principal Investigator: Rahul Aggarwal, MD

Sponsors and Collaborators

Rahul Aggarwal

AstraZeneca

Investigators

• Principal Investigator: Rahul Aggarwal; University of California, San Francisco

More Information

• Responsible Party: Rahul Aggarwal, Associate Clinical Professor, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT03682289
• Other Study ID Numbers: 189510; NCI-2018-01648 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
• First Posted: September 24, 2018
• Last Update Posted: April 6, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Carcinoma; Neoplasms; Pancreatic Neoplasms; Carcinoma, Renal Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Digestive System Neoplasms; Neoplasms by Site; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Adenocarcinoma; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Kidney Diseases; Urologic Diseases; Olaparib; Adenosine; Poly(ADP-ribose) Polymerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Vasodilator Agents