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, or other solid tumors 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:
  • Malignant Solid Tumor
  • Pancreatic Carcinoma
  • Renal Cell 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 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 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:

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

          -  Histologically confirmed locally advanced or metastatic solid tumor malignancy with by
             tumor type as specified below:

               -  Renal cell carcinoma with clear cell component (Cohort A): Patients must have
                  prior progression on or following, intolerance of, or patient refusal to receive
                  vascular endothelial growth factor (VEGF)-targeting tyrosine kinase inhibitor and
                  immune checkpoint blockade.

               -  Urothelial carcinoma (Cohort B). Patients must have prior progression on or
                  following, intolerance of, or patient refusal to receive platinum chemotherapy
                  and immune checkpoint blockade.

               -  All pancreatic cancers (Cohort C). Patients must have prior progression on or
                  following, intolerance of, or patient refusal to receive fluorouracil (5-FU),
                  gemcitabine, and irinotecan-based chemotherapy.

               -  Other solid tumors excluding clear cell ovarian cancer (Cohort D). Patients must
                  have prior progression on or following, intolerance of, of patient refusal of at
                  least one systemic therapy for locally advanced or metastatic disease and must
                  not have any curative treatment options available.

          -  Evidence of clinical or radiographic progression prior to study entry.

          -  Formalin-fixed paraffin embedded tumor tissue evaluable for BAF250a expression by
             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.

          -  Measurable disease by RECIST 1.1.

          -  Resolution of all prior treatment-related toxicities to grade 1 severity or lower
             (except alopecia).

          -  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.

          -  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.

          -  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).

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          -  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.

          -  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.

          -  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:

          -  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), ductal carcinoma in situ,
             stage I uterine cancer, and non-muscle invasive urothelial carcinoma.

          -  Patients receiving, or having received within 14 days of C1D1, corticosteroids at a
             dose > 10 mg/day of prednisone (or equivalent).

          -  Patients with myelodysplastic syndrome or features suggestive of myelodysplastic
             syndrome.

          -  Prior treatment with ATR or PARP inhibitor (e.g. olaparib, rucaparib, niraparib).

          -  Major surgical procedures < 28 days prior to C1D1. Patients must have recovered to
             grade =< 1 for any adverse events related to the surgical procedure.

          -  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.

          -  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.

          -  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.

          -  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).

          -  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.

          -  Relative hypotension with resting blood pressure of less than 90 mm Hg systolic and
             less than 60 mm Hg diastolic or symptomatic orthostatic hypotension.

          -  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.

          -  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).

          -  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.

          -  Known chronic active hepatitis B or C (defined by positive viral load; screening not
             required).

          -  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) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
Time Frame:Up to 2.5 years
Safety Issue:
Description: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:Will be summarized using Kaplan-Meier estimates with associated 95% confidence limits.
Measure:Median progression-free survival (PFS)
Time Frame:At 6 months
Safety Issue:
Description:Will be summarized using Kaplan-Meier estimates with associated 95% confidence limits.
Measure:Median PFS
Time Frame:At 12 months
Safety Issue:
Description:Will be summarized using Kaplan-Meier estimates with associated 95% confidence limits.
Measure:PFS rate
Time Frame:At 6 months
Safety Issue:
Description:Will be summarized as a proportion with an exact binomial 95% confidence interval.
Measure:PFS rate
Time Frame:At 12 months
Safety Issue:
Description:Will be summarized as a proportion with an exact binomial 95% confidence interval.
Measure:Incidence of adverse events per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time Frame:Up to 30 days post treatment
Safety Issue:
Description:Safety analyses will be descriptive summaries of adverse events (AEs) by patient and type.

Details

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

Last Updated

May 22, 2019