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Olaparib in Treating Patients With Metastatic or Advanced Urothelial Cancer With DNA-Repair Defects

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ClinicalTrials.gov Identifier: NCT03375307
Recruitment Status : Recruiting
First Posted : December 18, 2017
Last Update Posted : October 15, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE December 15, 2017
First Posted Date  ICMJE December 18, 2017
Last Update Posted Date October 15, 2019
Actual Study Start Date  ICMJE August 3, 2018
Estimated Primary Completion Date August 21, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 15, 2017)
Overall response rate (ORR) as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Up to 5 years ]
ORR will be reported along with 95% exact confidence intervals.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03375307 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 27, 2019)
  • Progression free survival (PFS) [ Time Frame: From the date of olaparib initiation to investigator-assessed clinical progression or radiographic progression (by RECIST), or death from any cause, whichever occurs first, assessed up to 5 years ]
    PFS will be determined using a Kaplan-Meier curve, with probabilities at various time points indicated along with appropriate confidence intervals.
  • Incidence of adverse events [ Time Frame: Up to 5 years ]
    Will be assessed according to the Common Terminology Criteria for Adverse Events version 5.0.
  • Individual deoxyribonucleic acid (DNA)-repair defects [ Time Frame: Up to 5 years ]
    The association between individual DNA-repair defects and ORR will be determined using Fisher's exact test.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 15, 2017)
  • Incidence of adverse events according to the Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 5 years ]
  • Individual deoxyribonucleic acid (DNA)-repair defects [ Time Frame: Up to 5 years ]
    The association between individual DNA-repair defects and ORR will be determined using Fisher's exact test.
  • Progression free survival (PFS) [ Time Frame: From the date of olaparib initiation to investigator-assessed clinical progression or radiographic progression (by RECIST), or death from any cause, whichever occurs first, assessed up to 5 years ]
    PFS will be determined using a Kaplan-Meier curve, with probabilities at various time points indicated along with appropriate confidence intervals.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Olaparib in Treating Patients With Metastatic or Advanced Urothelial Cancer With DNA-Repair Defects
Official Title  ICMJE A Phase II Study of Olaparib (AZD2281) in Patients With Metastatic/Advanced Urothelial Carcinoma With DNA-Repair Defects
Brief Summary This phase II trial studies how well olaparib works in treating patients with urothelial cancer with DNA-repair defects that has spread to other places in the body (advanced or metastatic) and usually cannot be cured or controlled with treatment. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the efficacy of olaparib in two cohorts of patients with metastatic/advanced urothelial carcinoma (UC) pre-selected by deoxyribonucleic acid (DNA)-repair defects as measured by overall response rate (ORR).

SECONDARY OBJECTIVES:

I. To describe the effect of therapy on progression free survival (PFS). II. To describe the effect of therapy on overall survival (OS). III. To describe the safety/tolerability and drug-related toxicities of olaparib.

CORRELATIVE OBJECTIVES:

I. To determine the proportion of patients with DNA-repair pathway-mutated genes in metastatic UC (patient cohort referred for screening).

II. To explore tumor-mutational profiles in metastatic tumor biopsies, saliva "normal" DNA, changes in tumor or peripheral immune characteristics, or tumor associated somatic mutation load in blood DNA in response to treatment.

III. To explore changes in plasma cytokines and correlate with clinical response.

IV. To correlate levels of circulating endothelial cells with clinical outcome. V. To correlate levels of circulating tumor cells (CTCs) with clinical outcome. VI. To correlate peripheral immune and DNA damage response transcriptional signatures with clinical outcomes.

VII. To determine the effectiveness of using next-generation sequencing (NGS) to identify DNA-repair pathway gene defects in tumor samples and circulating DNA and identify patients with UC suitable for PARP inhibition.

VIII. To determine the expression of Schlafen 11 (SLFN11) in tumor versus (vs.) stroma cells, and the potential tumor heterogeneity based on SLFN11 expression.

OUTLINE:

Patients receive olaparib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks, every 3 months for 1 year, and annually thereafter.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Abnormal DNA Repair
  • Advanced Urothelial Carcinoma
  • Metastatic Urothelial Carcinoma
  • Stage III Bladder Urothelial Carcinoma AJCC v6 and v7
  • Stage IV Bladder Urothelial Carcinoma AJCC v7
Intervention  ICMJE Drug: Olaparib
Given PO
Other Names:
  • AZD 2281
  • AZD-2281
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281
Study Arms  ICMJE Experimental: Treatment (olaparib)
Patients receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Drug: Olaparib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 27, 2019)
150
Original Estimated Enrollment  ICMJE
 (submitted: December 15, 2017)
60
Estimated Study Completion Date  ICMJE August 21, 2023
Estimated Primary Completion Date August 21, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the urothelial tract/bladder cancer
  • Patients must have Clinical Laboratory Improvement Act (CLIA) confirmed presence of a somatic or germline alteration considered pathogenic/likely pathogenic by FM and/or the Genetics Review Panel in one or more of the following genes: BRCA1, BRCA2, ATM, BAP1, FANCF, PALB2, and BRIP1 or in one or more of the DNA-repair genes tested in the FoundationOne FoundationOneCDx (F1CDx) panel including the following genes (Foundation One mutation analysis results and Foundation Liquid results performed prior to enrollment on this study may be accepted for eligibility review): ABL1, ATR, ATRX, BARD1, BLM, BRD4, CCND1, CHEK1, CHEK2, DOT1L, FANCC, FANCD2, FANCE, FANCG, FANCL, IKBKE, MEN1, MLH1, MSH2, MSH6, MUTYH, NPM1, PMS2, POLD1, POLE, PRKDC, RAD50, RAD51, SMARCB1, STK11

    • Note: FoundationOneCDx (F1CDx) is a next generation sequencing based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue specimens
  • Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
  • Evidence of disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1) during treatment or after the most recent dose of therapy with at least one platinum-based regimen of chemotherapy and/or an immune-checkpoint inhibitor (atezolizumab, pembrolizumab, nivolumab, avelumab or durvalumab) (2-week washout from chemotherapy and 4-weeks washout from monoclonal antibodies is required)
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (or Karnofsky >= 70%)
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (for subjects with documented Gilbert's disease total bilirubin =< 3.0 mg/dL)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (for subjects with liver metastasis AST/ALT =< 5 x ULN)
  • Creatinine clearance >= 50 mL/min/1.73 m^2
  • Hemoglobin >= 10 g/dL; transfusions are allowed
  • Prothrombin time (PT)/international normalized ratio (INR) and activated partial thromboplastin time (aPTT) within 1.25 x ULN institutional limits, except where a lupus anti-coagulant has been confirmed
  • Patients must be able to tolerate oral medications and not have gastrointestinal illnesses that would preclude absorption of olaparib
  • Pre-clinical data indicate that olaparib adversely affects embryofetal survival and development; therefore, women of child-bearing potential and their partners should agree to use two (2) highly effective forms of contraception throughout study participation and for at least one (1) month after the last dose of olaparib; male study participants should avoid fathering a child or donating sperm during the study and for three (3) months after the last dose of olaparib

    • Note: Olaparib is a PARP inhibitor with the potential for teratogenic or abortifacient effects; because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with olaparib, breastfeeding should be discontinued if the mother is treated with olaparib
  • Ability to understand and the willingness to sign a written informed consent document or patients with impaired decision making capacity (IDMC) if they are represented by a legally authorized representative (LAR)
  • Patients must provide tumor sample for mutation analysis or be willing to undergo mandatory screening biopsy
  • Patients must have a life expectancy >= 16 weeks
  • Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1

    • Postmenopausal is defined as:

      • Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
      • Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50
      • Radiation-induced oophorectomy with last menses > 1 year ago
      • Chemotherapy-induced menopause with >1 year interval since last menses
      • Surgical sterilization (bilateral oophorectomy or hysterectomy)
  • Patients is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations

Exclusion Criteria:

  • Patients with benign or variants of unknown significance as determined by FoundationOne FoundationOneCDx (F1CDx) panel and Genetics Review Panel review will be excluded
  • Patients who have had prior treatment with olaparib or any other PARP inhibitor (PARPi)
  • Patients with myelodysplastic syndrome/acute myeloid leukemia; or baseline features suggestive of myelodysplastic syndrome or acute myelogenous leukemia on peripheral blood smear or bone marrow biopsy, if clinically indicated
  • Persistent toxicities (>= Common Terminology Criteria for Adverse Events [CTCAE] grade 2) with the exception of alopecia, caused by previous cancer therapy
  • Patients who are receiving any other investigational agents; patients may be on other clinical trials or treatment during screening to determine eligibility
  • Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; a scan to confirm the absence of brain metastases is not required; patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition of olaparib
  • Patients receiving any medications or substances that are inhibitors or inducers of CYP3A are ineligible; a washout period prior to starting olaparib for patients on CYP3A inhibitors is 2 weeks; and the required washout period for CYP3A inducers is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents

    • Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference texts such as the Physicians' Desk Reference; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
  • Pregnant women are excluded from this study because olaparib is a PARP inhibitor agent with the potential for teratogenic or abortifacient effects
  • Any chronic or concurrent acute liver disease
  • History of stroke, transient ischemic attack (TIA), or myocardial infarction, within 6 months prior to enrollment
  • Uncontrolled concurrent disease or illness including but not limited to:

    • Ongoing or active infection
    • Symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia
    • Unstable or untreated cardiac conditions or ejection fraction of < 50% as determined by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA)
    • Uncontrolled diabetes mellitus
    • Psychiatric illness/social situations that would limit compliance with study requirements
  • Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for the study
  • Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV)
  • Patients with known active hepatitis (i.e., hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids
  • Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1 endometrial carcinoma, or other solid tumors including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for >= 5 years; patients with a history of localized triple negative breast cancer or localized resected prostate cancer may be eligible, provided they completed their adjuvant chemotherapy more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease
  • Resting electrocardiogram (ECG) with corrected QT (QTc) > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
  • Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 2 weeks prior to study treatment
  • Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
  • Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03375307
Other Study ID Numbers  ICMJE NCI-2017-02296
NCI-2017-02296 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
P162941
10144 ( Other Identifier: National Cancer Institute LAO )
10144 ( Other Identifier: CTEP )
ZIABC011078 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Andrea B Apolo National Cancer Institute LAO
PRS Account National Cancer Institute (NCI)
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP