Clinical Trials /

Testing Olaparib and AZD6738 in IDH1 and IDH2 Mutant Tumors

NCT03878095

Description:

This phase II trial studies how well olaparib and ceralasertib (AZD6738) work in treating patients with IDH mutant cholangiocarcinoma or solid tumors. Cancer is caused by changes (mutations) to genes that control the way cells function. Laboratory studies have shown that olaparib and AZD6738 can shrink IDH mutant tumors or stop them from growing. Olaparib and ceralasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing Olaparib and AZD6738 in IDH1 and IDH2 Mutant Tumors
  • Official Title: A Phase II Study of Olaparib and AZD6738 in Isocitrate Dehydrogenase (IDH) Mutant Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-01461
  • SECONDARY ID: NCI-2019-01461
  • SECONDARY ID: 10222
  • SECONDARY ID: 10222
  • SECONDARY ID: UM1CA186689
  • NCT ID: NCT03878095

Conditions

  • Malignant Solid Neoplasm
  • Refractory Cholangiocarcinoma
  • Refractory Malignant Solid Neoplasm

Interventions

DrugSynonymsArms
CeralasertibAZD6738Treatment (olaparib, ceralasertib)
OlaparibAZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP inhibitor AZD2281Treatment (olaparib, ceralasertib)

Purpose

This phase II trial studies how well olaparib and ceralasertib work in treating patients with IDH mutant cholangiocarcinoma or solid tumors. Cancer is caused by changes (mutations) to genes that control the way cells function. Laboratory studies have shown that olaparib and AZD6738 can shrink IDH mutant tumors or stop them from growing. Olaparib and ceralasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the overall response rates of olaparib and ceralasertib (AZD6738) in subjects
      with recurrent/progressive IDH1/2-mutant solid malignant tumors, who will be recruited to 2
      cohorts: a. Cholangiocarcinoma b. Other solid malignant tumors.

      SECONDARY OBJECTIVES:

      I. To determine the progression free survival (PFS) of olaparib and AZD6738 in adults with
      recurrent/progressive IDH1/2-mutant solid malignant tumors.

      II. To estimate the overall survival (OS) in adults with recurrent/progressive IDH1/2- mutant
      solid malignant tumors.

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

      IV. To assess the safety and tolerability of the combination of olaparib and AZD6738.

      EXPLORATORY OBJECTIVES:

      I. To evaluate 2-hydroxyglutarate (2HG) concentration in plasma by mass spectrometry and
      correlate with treatment response.

      II. To evaluate 2HG levels in tumor biopsies prior to the beginning of treatment and while on
      therapy and correlate with treatment response.

      III. Correlate 2HG concentration in plasma and in tumor biopsies. IV. To evaluate
      deoxyribonucleic acid (DNA) double strand breaks (DSBs) as measured by mass cytometry time of
      flight (CyTOF)-imaging mass cytometry (IMC) in tumor biopsies before and after treatment with
      olaparib and AZD6738.

      OUTLINE:

      Patients receive olaparib orally (PO) twice daily (BID) on days 1-28 and ceralasertib PO once
      daily (QD) on days 1-7. 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (olaparib, ceralasertib)ExperimentalPatients receive olaparib PO BID on days 1-28 and ceralasertib PO QD on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Ceralasertib
  • Olaparib

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 cholangiocarcinoma or other solid malignant tumor
             that has progressed despite standard therapy, or for which no effective standard
             therapy exists. Patients with primary central nervous system (CNS) tumors, e.g.
             glioma, are not allowed

          -  Patients must have biopsy-confirmed evidence of an IDH1 or IDH2 mutation, confirmed in
             a Clinical Laboratory Improvement Act (CLIA)-certified laboratory, associated with
             neomorphic activity of the encoded proteins

          -  Previous treatment with a poly adenosine diphosphate ribose polymerase (PARP)
             inhibitor is allowed

          -  Patients must have tumors determined to be easily accessible for biopsy and must be
             willing to have serial biopsies. Tumor biopsies will be performed on the most
             accessible biopsiable site of disease. All possible precautions to avoid complications
             will be taken, including discussions in multidisciplinary meetings, if needed. If a
             patient opts out of a pre-treatment biopsy, biopsy is not possible, or if a
             pre-treatment biopsy does not yield sufficient tissue for analysis, the patient must
             be willing to provide an archival formalin-fixed paraffin-embedded (FFPE) specimen, if
             available, for liquid chromatography/mass spectrometry (LC/MS) analysis of 2HG.
             Permission of the study principal investigator (PI) is required in all of the above
             scenarios

               -  In order to maximize the availability of newly obtained specimens for 2-HG
                  analysis, at least 10 biopsies will be required in each group (cholangiocarcinoma
                  and other solid tumors) of 14 patients treated in the first stage of this Simon
                  two-stage design

               -  All patients must be willing to provide 5 unstained archival slides, if
                  available, for pre-treatment 2-HG analysis and correlation with 2-HG levels in
                  pre-treatment frozen specimens

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

          -  Patients must have evaluable disease by Response Evaluation Criteria in Solid Tumors
             (RECIST) version (v)1.1

          -  Patients 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 callipers by clinical exam OR at least one
             lesion (measurable and/or non-measurable) that can be accurately assessed by
             CT/MRI/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 target ATR) 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 prior therapies should have recovered to =< grade 1, with the
             exception of stable chronic grade 2 toxicities that are not overlapping with presumed
             toxicities of olaparib

          -  Patients with treated brain metastases are eligible if there is no evidence of
             progression for at least 4 weeks after central nervous system (CNS)-directed
             treatment, as ascertained by clinical examination and brain imaging (MRI or CT scan)
             during the screening period

          -  Patients with new or progressive brain metastases (active brain metastases) or
             leptomeningeal disease are eligible if the treating physician determines that
             immediate CNS specific treatment is not required and is unlikely to be required for at
             least 4 weeks (or scheduled assessment after the first cycle of treatment), and a
             risk-benefit analysis (discussion) by the patient and the investigator favors
             participation in the clinical trial

          -  If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be
             undetectable on suppressive therapy if indicated. If history of hepatitis C virus
             (HCV) infection, must be treated with undetectable HCV viral load

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

          -  Hemoglobin >= 10.0 g/dL with no blood transfusion in < 14 days prior to starting
             therapy (measured within 14 days prior to administration of study treatment)

          -  Leukocytes >= 3,000/mcL (measured within 14 days prior to administration of study
             treatment)

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (measured within 14 days prior to
             administration of study treatment)

          -  Platelet count >= 100 x 10^9/L (measured within 14 days prior to administration of
             study treatment)

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (measured within 14
             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 (measured within 14 days prior to administration of study
             treatment)

          -  Creatinine clearance estimated using the Cockcroft-Gault equation of >= 51 mL/min or
             based on a 24 hour urine test (measured within 14 days prior to administration of
             study treatment)

          -  No features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
             on peripheral blood smear

          -  Patients must have a life expectancy of >= 16 weeks, in the opinion of the treating
             physician

          -  Patients must be 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

          -  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 6 months 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:

                    -  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 6 months after
             last dose of study drug(s) to prevent pregnancy in a partner

          -  Patients with human immunodeficiency virus (HIV) on effective antiretroviral therapy
             with undetectable viral load within 6 months are eligible for this trial

        Exclusion Criteria:

          -  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

          -  Any previous treatment with AZD6738 or any other ATR inhibitor

          -  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 electrocardiography (ECG) indicating uncontrolled, potentially reversible
             cardiac conditions, as judged by the investigator (eg., unstable ischemia,
             uncontrolled symptomatic arrhythmia, congestive heart failure, Fridericia's corrected
             QT [QTcF] prolongation > 500 ms, electrolyte disturbances, etc.), or patients with
             congenital long QT syndrome

          -  Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,
             clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
             saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
             ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
             period prior to starting olaparib is 5 half-lives

          -  Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,
             rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St .John's wort) or
             moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout
             period prior to starting olaparib is 3 weeks for St. John's wort and 5 half lives for
             other agents

          -  Persistent toxicities caused by previous cancer therapy. Toxicities should have
             recovered to =< grade 1, excluding alopecia, or should be stable chronic grade 2
             toxicities that do not overlap with presumed toxicities of olaparib and/or AZD6738

          -  Patients with myelodysplastic syndrome/acute myeloid leukemia or with features
             suggestive of MDS/AML

          -  Patients with new or progressive brain metastases (active brain metastases) or
             leptomeningeal disease are not eligible if the treating physician determines that
             immediate CNS specific treatment is required, and a risk-benefit analysis (discussion)
             by the patient and the investigator does not favor participation in the clinical
             trial. 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

          -  Major surgery within 2 weeks of starting study treatment. Major surgeries typically
             require general anesthesia, are associated with an estimated blood loss of > 500 mL,
             and require an overnight hospital stay. Examples include laparoscopic surgery, open
             resection of organs, joint replacements and other orthopedic surgeries, and vascular
             or intracranial surgeries. Examples of minor surgeries include those performed on an
             ambulatory basis, cataract surgery, dental surgeries, cutaneous, endoscopic, and
             arthroscopic procedures. Effects from major surgeries should have recovered to =<
             grade 1, with the exception of stable chronic grade 2 toxicities that are not
             overlapping with presumed toxicities of olaparib and/or AZD6738

          -  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

          -  Patients with a known hypersensitivity to olaparib or AZD6738 or any of the excipients
             of the products. History of allergic reactions attributed to compounds of similar
             chemical or biologic composition to olaparib or AZD6738

          -  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 within the last 28 days)

          -  Patients who are receiving any other investigational agents

          -  Pregnant women are excluded from this study because olaparib is an agent with the
             potential for teratogenic or abortifacient effects. Because there is an unknown but
             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

          -  Receiving, or having received during the 14 days prior to first dose, corticosteroids
             (at a dose > 10 mg prednisone/day or equivalent) for any reason

          -  Any of the following cardiac diseases currently or within the last 6 months (by New
             York Heart Association (NYHA) >= class 2 where applicable):

               -  Unstable angina pectoris

               -  Congestive heart failure or known reduced left ventricular ejection fraction
                  (LVEF) < 55%

               -  Acute myocardial infarction

               -  Conduction abnormality not controlled with pacemaker or medication e.g. complete
                  left bundle branch block, third degree heart block

               -  Significant ventricular or supraventricular arrhythmias e.g. (patients with
                  chronic rate-controlled atrial fibrillation in the absence of other cardiac
                  abnormalities are eligible)

          -  Patients at risk of brain perfusion problems, e.g., medical history of carotid
             stenosis or pre-syncopal or syncopal episodes, history of transient ischemic attacks
             (TIAs)

          -  Uncontrolled hypertension (grade 2 or above) requiring clinical intervention

          -  Any factors that increase the risk of corrected QT (QTc) prolongation or risk of
             arrhythmic events such as congestive heart failure, unstable angina pectoris, acute
             myocardial infarction, hypokalemia, congenital long QT syndrome, immediate family
             history of long QT syndrome or unexplained sudden death under 40 years of age,
             conduction abnormality not controlled with pacemaker or medication

          -  Patients with relative hypotension (< 90/60 mm Hg) or clinically relevant orthostatic
             hypotension, including a fall in blood pressure of > 20 mm Hg

          -  Refractory nausea and vomiting, chronic gastrointestinal diseases o
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:Up to 30 days post treatment after removal from study
Safety Issue:
Description:The exact two-sided 95% confidence intervals (CIs) for the ORR will be reported.

Secondary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed up to 30 days after removal from study
Safety Issue:
Description:PFS will be estimated using the Kaplan-Meier method with the 95% CIs. The 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.
Measure:Overall survival (OS)
Time Frame:From start of treatment to time of death, assessed up to 30 days after removal from study
Safety Issue:
Description:OS will be estimated using the Kaplan-Meier method with the 95% CIs. The 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.
Measure:Duration of response
Time Frame:From the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 30 days after removal from study
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method with the 95% CIs. The 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.
Measure:Incidence of adverse events
Time Frame:Up to 30 days post treatment
Safety Issue:
Description:Toxicities will be evaluated utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

January 16, 2020