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

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Brief Title

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

Official Title

A Phase 2 Study of the PARP Inhibitor Olaparib (AZD2281) in IDH1 and IDH2 Mutant Advanced Solid Tumors

Brief Summary

      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 (metastatic) and usually cannot be cured or controlled with treatment
      (refractory). Olaparib may stop the growth of tumor cells by blocking some of the enzymes
      needed for cell growth.
    

Detailed Description

      PRIMARY OBJECTIVE:

      I. To estimate the overall response rates of olaparib in subjects with recurrent/progressive
      IDH1/2-mutant solid tumors, who will be recruited to 3 cohorts: a. glioma, b.
      cholangiocarcinoma, c. other solid malignant tumors.

      SECONDARY OBJECTIVES:

      I. To estimate the distribution of progression free survival (PFS) of olaparib in adults with
      recurrent/progressive IDH1/2-mutant glioma and cholangiocarcinoma.

      II. To estimate the overall survival (OS) in adults with recurrent/progressive IDH1/2- mutant
      glioma and cholangiocarcinoma.

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

      IV. To confirm the safety and tolerability of olaparib monotherapy.

      EXPLORATORY OBJECTIVES:

      I. To describe 2HG concentration in plasma by mass spectrometry at baseline and at specific
      timepoints and correlate with treatment response.

      II. To describe 2HG levels in tumor biopsies from prior to the beginning of treatment and at
      specific timepoints and correlate with treatment response.

      III. To evaluate in tumor biopsies and in liquid biopsies performed at baseline and at
      specific timepoints if co-occurring alterations detected via multiplexed immunofluorescence,
      mass cytometry (CyTOF)-imaging mass cytometry (IMC), ribonucleic acid (RNA) sequencing and/or
      deoxyribonucleic acid (DNA) sequencing can be associated with differential levels of 2HG
      production, treatment response and resistance.

      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 for 30 days.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Overall response rate

Secondary Outcome

 Progression-free survival

Condition

Advanced Malignant Solid Neoplasm

Intervention

Olaparib

Study Arms / Comparison Groups

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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

145

Start Date

March 30, 2018

Completion Date

July 31, 2021

Primary Completion Date

July 31, 2021

Eligibility 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; patients with Impaired
             Decision Making Capacity (IDMC) who have a close caregiver or legally authorized
             representative (LAR) may be considered eligible for this study at the treating
             physician's discretion, provided that the physician is reasonably sure that the
             possible risks and benefits of the study are clear and that the patient will take the
             drug as prescribed

          -  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 have IDH1 or IDH2
             mutation which must be detected in a clinical accredited laboratory using a Food and
             Drug Administration (FDA)-approved molecular test or a validated deoxyribonucleic acid
             (DNA)-based assay conducted in a Clinical Laboratory Improvement Amendments
             (CLIA)-certified laboratory; only specific mutations that lead to a neomorphic
             phenotype will be eligible for enrollment, and include IDH1: R132V, R132G, R132S,
             R132L, R132C and R132H; IDH2: R140W, R140L, R140Q, R172W, R172G, R172S, R172M, R172K

          -  Patients must have tumors determined to be easily accessible for biopsy and must be
             willing to have serial biopsies (with a third biopsy upon evidence of disease
             progression); in case of multiple lesions, tumor biopsies will be performed on the
             most accessible site of disease; all possible precautions to avoid complications will
             be taken, including discussions in multidisciplinary meetings, if needed; patients
             affected by glioma will not be considered for study biopsies

          -  Patients must be willing to undergo extra blood sampling for correlative studies

          -  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 Response Assessment in Neuro-Oncology Criteria (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 3 weeks 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-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; toxicities from these therapies should have recovered to =< grade 1,
             with the exception of stable chronic grade 2 that is not overlapping with presumed
             toxicities of olaparib

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky >= 50%)

          -  Hemoglobin >= 10.0 g/dL with no blood transfusion in the past 28 days (within 28 days
             prior to administration of study treatment)

          -  Leukocytes >= 3,000/mcL (within 28 days prior to administration of study treatment)

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 28 days prior to
             administration of study treatment)

          -  Platelet count >= 100 x 10^9/L (within 28 days prior to administration of study
             treatment)

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 28 days
             prior to administration of study treatment)

          -  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 (within 28 days prior to administration of study
             treatment)

          -  Creatinine clearance estimated using the Cockcroft-Gault equation of >= 51 mL/min
             (within 28 days prior to administration of study treatment)

          -  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 PARP
             inhibitor

          -  Prior radiation therapy is allowed; patients must not have received radiation therapy
             within 3 weeks prior to the initiation of study treatment

          -  Women of child-bearing potential are expected to use highly effective contraception
             during the study and for 1 month after the last dose of study drug; 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 one or more of the following:

               -  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 less) 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 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; because the lists of these agents are
             constantly changing, it is important to regularly consult a frequently updated drug
             information reference; medical reference texts such as the Physicians' Desk Reference
             may also provide this information; 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

          -  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; because the lists of these agents are constantly changing, it
             is important to regularly consult a frequently updated drug information reference;
             medical reference texts such as the Physicians' Desk Reference may also provide this
             information; 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

          -  Persistent toxicities caused by previous cancer therapy; toxicities should have
             recovered to =< grade 1, excluding alopecia and stable chronic grade 2 toxicity that
             is not overlapping with presumed toxicities of olaparib

          -  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 because of their poor prognosis and because they often develop
             progressive neurologic dysfunction that would confound the evaluation of neurologic
             and other adverse events

          -  Major surgery within 2 weeks of starting study treatment; effects from surgeries
             should have recovered to =< grade 1, with the exception of stable chronic grade 2 that
             is not overlapping with presumed toxicities of olaparib

          -  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 because of the potential for pharmacokinetic
             interactions with Olaparib; in addition, these patients are at increased risk of
             lethal infections when treated with marrow-suppressive therapy; appropriate studies
             will be undertaken in patients receiving combination antiretroviral therapy when
             indicated

          -  Patients with a known hypersensitivity to olaparib or any of the excipients of the
             product; history of allergic reactions attributed to compounds of similar chemica
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Patricia M LoRusso, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03212274

Organization ID

NCI-2017-01182

Secondary IDs

NCI-2017-01182

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Patricia M LoRusso, Principal Investigator, Yale University Cancer Center LAO


Verification Date

May 2020