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Phase II Trial of AZD6738 Alone and in Combination With Olaparib

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ClinicalTrials.gov Identifier: NCT03682289
Recruitment Status : Not yet recruiting
First Posted : September 24, 2018
Last Update Posted : October 23, 2018
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco

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, pancreatic ductal adenocarcinoma, 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.

Condition or disease Intervention/treatment Phase
Clear Cell Renal Cell Carcinoma Locally Advance Pancreatic Ductal Adenocarcinoma Locally Advanced Malignant Solid Neoplasm Metastatic Malignant Solid Neoplasm Metastatic Renal Cell Carcinoma Metastatic Urothelial Carcinoma Pancreatic Ductal Adenocarcinoma Stage III Pancreatic Cancer AJCC v8 Stage III Renal Cell Cancer AJCC v8 Stage IV Pancreatic Cancer AJCC v8 Stage IV Renal Cell Cancer AJCC v8 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 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
Estimated Study Start Date : December 1, 2018
Estimated Primary Completion Date : March 19, 2021
Estimated Study Completion Date : March 19, 2023


Arm Intervention/treatment
Experimental: Arm I (ATR kinase inhibitor AZD6738)
Participants who are BAF250a negative receive ATR kinase inhibitor AZD6738 PO BID on days 1-14. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: ATR Kinase Inhibitor AZD6738
Given PO
Other Names:
  • AZD-6738
  • AZD6738

Experimental: Arm II (ATR kinase inhibitor AZD6738, olaparib)
Participants who are BAF250a positive receive ATR kinase inhibitor AZD6738 PO QD on days 1-7 and olaparib PO BID on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: ATR Kinase Inhibitor AZD6738
Given PO
Other Names:
  • AZD-6738
  • AZD6738

Drug: Olaparib
Given PO
Other Names:
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281




Primary Outcome Measures :
  1. Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria [ Time Frame: Up to 2.5 years ]
    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 ]
    Will be summarized using Kaplan-Meier estimates with associated 95% confidence limits.

  2. Median progression-free survival (PFS) [ Time Frame: At 6 months ]
    Will be summarized using Kaplan-Meier estimates with associated 95% confidence limits.

  3. Median PFS [ Time Frame: At 12 months ]
    Will be summarized using Kaplan-Meier estimates with associated 95% confidence limits.

  4. PFS rate [ Time Frame: At 6 months ]
    Will be summarized as a proportion with an exact binomial 95% confidence interval.

  5. PFS rate [ Time Frame: At 12 months ]
    Will be summarized as a proportion with an exact binomial 95% confidence interval.

  6. 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 analyses will be descriptive summaries of adverse events (AEs) by patient and type.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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.
    • Pancreatic ductal adenocarcinoma (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 < 90/60 mm Hg 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 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.

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): NCT03682289


Contacts
Contact: Rahul Aggarwal 877-837-3222 cancertrials@ucsf.edu

Locations
United States, California
UCSF Medical Center-Mount Zion Not yet recruiting
San Francisco, California, United States, 94115
Contact: Rahul R. Aggarwal    877-837-3222      
Principal Investigator: Rahul R. Aggarwal, MD         
Sponsors and Collaborators
University of California, San Francisco
Investigators
Principal Investigator: Rahul Aggarwal UCSF Medical Center-Mount Zion

Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03682289     History of Changes
Other Study ID Numbers: 189510
NCI-2018-01648 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: September 24, 2018    Key Record Dates
Last Update Posted: October 23, 2018
Last Verified: October 2018
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
Adenocarcinoma
Pancreatic Neoplasms
Carcinoma, Renal Cell
Carcinoma, Transitional 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
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Kidney Diseases
Urologic Diseases
Olaparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents