Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma

Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations

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https://clinicaltrials.gov/ct2/show/NCT03212274

Purpose
This phase II trial studies how well olaparib works in treating patients with glioma, cholangiocarcinoma, or solid tumors with IDH1 or IDH2 mutations that have spread to other places in the body 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.

Condition Intervention Phase
Advanced Malignant Solid Neoplasm
Glioblastoma
Grade II Glioma
IDH1 Gene Mutation
IDH2 Gene Mutation
Recurrent Cholangiocarcinoma
Recurrent Glioma
Recurrent Malignant Solid Neoplasm
WHO Grade III Glioma
Other: Laboratory Biomarker Analysis
Drug: Olaparib
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Phase 2 Study of the PARP Inhibitor Olaparib (AZD2281) in IDH1 and IDH2 Mutant Advanced Solid Tumors

Resource links provided by NLM:

Genetics Home Reference related topics: cholangiocarcinoma
Drug Information available for: Olaparib
Genetic and Rare Diseases Information Center resources: Glioblastoma Glioma Neuroepithelioma
U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
Overall response rate as determined by investigator assessment using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) for extracranial solid tumors, Response Assessment in Neuro-Oncology (RANO) criteria for intracranial glioma [ Time Frame: Up to completion of course 8 ]
The exact two-sided 95% confidence intervals for the overall response rate will be reported. Overall response rate will be determined by the sum of the number of patients determined to be either complete response (CR) or partial response (PR) divided by the total number of eligible patients. Patients with missing or no response assessments will be removed from the analysis.

Secondary Outcome Measures:
Progression-free survival (PFS) [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year ]
The possible risk factors will be compared for survival with Kaplan-Meier estimates with the 95% confidence intervals (Cis) and log-rank tests. The confidence interval (CI) based on the Greenwoods variance will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease on the survival data. The adjusted p-values of the odds ratios and the adjusted 95% confidence interval will be reported.

Other Outcome Measures:
2HG plasma concentration level [ Time Frame: Up to 1 year ]
Biomarker data analysis will be completed using the Lasso based elastic net method. The penalty parameter that controls the shrinkage of fixed terms and the variable selection will be determined by k-fold cross validation. Analytical methods for comparison of 2HG plasma concentrations will be performed using the Mann-Whitney U test.

2HG plasma magnetic resonance spectroscopy (MRS) levels [ Time Frame: Baseline up to post-treatment ]
Biomarker data analysis will be completed using the Lasso based elastic net method. The penalty parameter that controls the shrinkage of fixed terms and the variable selection will be determined by k-fold cross validation. 1H MRS metabolite 2HG levels will be compared using analysis of variance (ANOVA) for repeated measures.

Estimated Enrollment: 75
Anticipated Study Start Date: March 30, 2018
Estimated Study Completion Date: July 31, 2018
Estimated Primary Completion Date: July 31, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (olaparib)
Patients receive olaparib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Olaparib
Given PO
Other Names:
AZD2281
KU-0059436
Lynparza
PARP Inhibitor AZD2281

Detailed Description:
PRIMARY OBJECTIVES:

I. To determine the overall response rates of olaparib in subjects with recurrent/progressive IDH1/2-mutant glioma, cholangiocarcinoma or other solid malignant tumors.

SECONDARY OBJECTIVES:

I. To determine the progression-free survival (PFS) of olaparib in adults with recurrent/progressive IDH1/2-mutant glioma, cholangiocarcinoma or other solid malignant tumors.

II. To determine the duration of response in adults with recurrent/progressive IDH1/2-mutant glioma, cholangiocarcinoma or other solid malignant tumors.

III. Confirm the safety and tolerability of olaparib monotherapy.

TERTIARY OBJECTIVES:

I. To evaluate 2-hydroxyglutarate (2HG) 1H magnetic resonance spectroscopy (MRS) signal in patients with intracranial glioma and correlate with treatment response prior to beginning treatment and after cycles 2, 4 and 8 of therapy and at time of confirmed evidence of progression.

II. To evaluate 2HG concentration in plasma by mass spectrometry and correlate with treatment response, prior to beginning treatment and after cycles 2, 4 and 8 of therapy and at time of confirmed evidence of progression.

III. To evaluate 2HG levels in tumor biopsies from prior to the beginning of treatment and correlate with treatment response.

OUTLINE:

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

After completion of study treatment, patients are followed up for 30 days.

Eligibility

Ages Eligible for Study: 18 Years and older (Adult, Senior)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:

Subjects must be able to understand the nature of this trial and provide written informed consent, prior to any study specific procedures
Subjects must be diagnosed with a glioma, cholangiocarcinoma or other solid malignant tumor that has progressed despite standard therapy, or for which no effective standard therapy exists, with biopsy-confirmed evidence of an IDH1 or IDH2 mutation associated with neomorphic activity of the encoded proteins
Patients must be willing to provide archival formalin-fixed paraffin-embedded (FFPE) or frozen specimens for central analysis, if available; if no adequate archival tumor biopsy is available, patients must undergo a new biopsy
Patients with previously identified IDH1/2 mutations can be enrolled on the trial, but must be verified in the central study laboratory
Subjects with extracranial disease must have evaluable disease by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1); subjects affected by glioma must have evaluable disease by RANO criteria
For subjects with glioma, specific inclusion criteria are as follows:

The disease should be recurrent or transformed glioma; subjects must not have had prior surgery (biopsy allowed) or radiation therapy within 30 days of enrollment
There must be an enhancing component of disease, as evaluated on pre-treatment magnetic resonance imaging (MRI)
For patients with World Health Organization (WHO) grade III or IV glioma and progressive disease < 12 weeks after completion of chemoradiotherapy, progression can be defined by the following set of criteria: New enhancement outside of the radiation field (beyond the high-dose region or 80% isodose line)
If there is unequivocal evidence of viable tumor on histopathologic sampling (e.g., solid tumor areas. i.e., > 70% tumor cell nuclei in areas), high or progressive increase in MIB-1 proliferation index compared with prior biopsy, or evidence for histologic progression or increased anaplasia in tumor);
Note: Given the difficulty of differentiating true progression from pseudoprogression, clinical decline alone, in the absence of radiographic or histologic confirmation of progression, will not be sufficient for definition of progressive disease in the first 12 weeks after completion of concurrent chemoradiotherapy
For patients with WHO grade III or IV glioma and progressive disease >= 12 weeks after completion of chemoradiotherapy, progression can be defined by the following set of criteria:

New contrast-enhancing lesion outside of radiation field on decreasing, stable, or increasing doses of corticosteroids
Increase by >= 25% in the sum of the products of perpendicular diameters between the first post-radiotherapy scan, or a subsequent scan with smaller tumor size, and the scan at 12 weeks or later on stable or increasing doses of corticosteroids
For patients receiving antiangiogenic therapy, significant increase in T2/fluid attenuated inversion recovery (FLAIR) non-enhancing lesion may also be considered progressive disease; the increased T2/FLAIR must have occurred with the patient on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy and not be a result of comorbid events (e.g., effects of radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or other treatment effects)
Note: Clinical deterioration alone is not attributable to concurrent medication or comorbid conditions is sufficient to declare progression on current treatment but not for entry onto a clinical trial for recurrence
For patients with WHO grade II glioma progression is defined by any one of the following:

Development of new lesions or increase of enhancement (radiological evidence of malignant transformation)
A 25% increase of the T2 or FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not attributable to radiation effect or to comorbid events
For subject with extracranial disease, they must have at least one lesion, not previously irradiated, that can be accurately measured at baseline as >= 10 mm in the longest diameter (except lymph nodes which must have short axis >= 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) or >= 10 mm with calipers by clinical exam OR at least one lesion (measurable and/or non-measurable) that can be accurately assessed by CT/MRI/pain x-ray/clinical exam at baseline and follow up visits
Subjects must have progressive cancer at the time of study entry; prior experimental (non-Food and Drug Administration [FDA] approved) therapies (other than drugs that share the same target) and immunotherapies are allowed; patients must not have received these therapies for 30 days or five half-lives of the drug (whichever is less) prior to the initiation of study treatment and must have full recovery from any acute effects of these therapies
Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 80%)
Hemoglobin >= 10.0 g/dL with no blood transfusion in the past 28 days
Leukocytes >= 3,000/mcL
Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
Platelet count >= 100 x 10^9/L
Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be =< 5 x ULN
Patients must have creatinine clearance estimated using the Cockcroft-Gault equation of >= 51 mL/min
No features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) on peripheral blood smear
Patients must have a life expectancy >= 16 weeks
Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
No previous treatment with the specific assigned study drug or any other drug sharing the same target
Prior radiation therapy is allowed; patients must not have received radiation therapy within 4 weeks prior to the initiation of study treatment
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)
Male patients and their partners, who are sexually active and of childbearing potential, must agree to the use of two highly effective forms of contraception in combination, throughout the period of taking study treatment and for 3 months after last dose of study drug(s) to prevent pregnancy in a partner
Exclusion Criteria:

Patients should not enter the study if any of the following exclusion criteria are fulfilled
Involvement in the planning and/or conduct of the study
Previous enrollment in the present study
Participation in another clinical study with an investigational product during the last 30 days or five half-lives of the drug (whichever is greater) prior to the initiation of study treatment (6 weeks for nitrosoureas or mitomycin C)
Any previous treatment with PARP inhibitor, including olaparib
Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment
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 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 interval (QTc) > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil); the required washout period prior to starting olaparib is 2 weeks
Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil); the required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
Persistent toxicities (> Common Terminology Criteria for Adverse Event [CTCAE] grade 2) caused by previous cancer therapy, excluding alopecia
Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML
Patients with symptomatic uncontrolled brain metastases; a scan to confirm the absence of brain metastases is not required; the patient can receive a stable dose of corticosteroids before and during the study if these were started at least 4 weeks prior to treatment; patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days; patients with known uncontrolled brain metastases should be excluded from this clinical trial
Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection; examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent and would limit compliance with study requirements
Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
Women who are actively breast feeding
Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV); HIV-positive patients on combination antiretroviral therapy are ineligible
Patients with a known hypersensitivity to olaparib or any of the excipients of the product
Patients with a known hypersensitivity to the combination/comparator agent
Patients with known active hepatitis (i.e. hepatitis B or C)
Previous allogeneic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable)
Patients who are receiving any other investigational agents
History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib
Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with olaparib
Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03212274

Locations
United States, Connecticut
Yale University Cancer Center LAO Not yet recruiting
New Haven, Connecticut, United States, 06520
Contact: Ranjit S. Bindra 203-200-3673 ranjit.bindra@yale.edu
Principal Investigator: Ranjit S. Bindra
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Ranjit Bindra Yale University Cancer Center LAO
More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03212274 History of Changes
Other Study ID Numbers: NCI-2017-01182
NCI-2017-01182 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10129 ( Other Identifier: Yale University Cancer Center LAO )
10129 ( Other Identifier: CTEP )
UM1CA186689 ( U.S. NIH Grant/Contract )
Study First Received: July 7, 2017
Last Updated: July 7, 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Neoplasms
Glioblastoma
Glioma
Cholangiocarcinoma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Adenocarcinoma
Carcinoma
Poly(ADP-ribose) Polymerase Inhibitors
Olaparib
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents

ClinicalTrials.gov processed this record on July 12, 2017