Clinical Trials /

Phase II Trial of AZD6738 Alone and in Combination With Olaparib

NCT03682289

Description:

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.

Related Conditions:
  • Clear Cell Renal Cell Carcinoma
  • Malignant Solid Tumor
  • Pancreatic Carcinoma
  • Prostate Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II Trial of AZD6738 Alone and in Combination With Olaparib
  • Official Title: Phase II Trial of AZD6738 Alone and in Combination With Olaparib in Patients With Selected Solid Tumor Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 189510
  • SECONDARY ID: NCI-2018-01648
  • NCT ID: NCT03682289

Conditions

  • 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

Interventions

DrugSynonymsArms
ATR Kinase Inhibitor AZD6738AZD-6738, AZD6738Arm I (ATR kinase inhibitor AZD6738)
OlaparibAZD2281, KU-0059436, Lynparza, poly adenosine diphosphate-ribose polymerase (PARP) inhibitor AZD2281Arm II (ATR kinase inhibitor AZD6738, olaparib)

Purpose

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, or 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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (ATR kinase inhibitor AZD6738)ExperimentalParticipants 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.
  • ATR Kinase Inhibitor AZD6738
Arm II (ATR kinase inhibitor AZD6738, olaparib)ExperimentalParticipants 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.
  • ATR Kinase Inhibitor AZD6738
  • Olaparib

Eligibility 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 (Cohort D)

               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 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:Up to 2.5 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Median duration of response (DOR)
Time Frame:Up to 2.5 years
Safety Issue:
Description:Summarized using Kaplan-Meier estimates with associated 95% confidence limits.
Measure:Median progression-free survival (PFS)
Time Frame:Up to 12 months
Safety Issue:
Description:Summarized using Kaplan-Meier estimates with associated 95% confidence limits at 6 and 12 months
Measure:Progression-free survival (PFS) rate over time
Time Frame:Up to 12 months
Safety Issue:
Description:The PFS rate at 6 and 12 months endpoint will be summarized as a proportion with an exact binomial 95% confidence interval.
Measure:Number of treatment-related adverse events (AEs)
Time Frame:Up to 30 days post treatment
Safety Issue:
Description: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
Measure:Prostate Cancer Patient Response Rate
Time Frame:Up to 12 months
Safety Issue:
Description: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
Measure:Prostate Cancer Patient Progression Free Survival
Time Frame:Up to 12 months
Safety Issue:
Description:In prostate cancer patients only, to determine the radiographic progression-free survival by PCWG3 criteria

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Rahul Aggarwal

Last Updated

June 9, 2020