Clinical Trials /

OLAParib COmbinations

NCT02576444

Description:

The primary objective of this phase II trial is to determine tumor overall response rate (ORR) in molecularly selected patients with measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), before versus after 16 weeks of treatment across tumor types in each arm of the study.

Related Conditions:
  • Cholangiocarcinoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: OLAParib COmbinations
  • Official Title: A Phase II Study of the PARP Inhibitor Olaparib (AZD2281) Alone and in Combination With AZD1775, AZD5363, or AZD6738 in Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: 1508016363
  • NCT ID: NCT02576444

Conditions

  • Cancer

Interventions

DrugSynonymsArms
AZD2281OlaparibGroup 1
AZD5363Group 2
AZD1775Group 3
AZD6738Group 4

Purpose

The primary objective of this phase II trial is to determine tumor overall response rate (ORR) in molecularly selected patients with measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), before versus after 16 weeks of treatment across tumor types in each arm of the study.

Detailed Description

      This is a phase II signal-searching study in a range of tumor types with the potential to
      identify novel tumor indications for combination therapy with olaparib that can subsequently
      be explored in dedicated studies. Patients will be enrolled in this study based on molecular
      markers from genetic profiling performed on their tumors prior to study entry (outside of
      protocol). The trial will also identify genetic determinants of response and resistance.

      Patients with tumors harboring damaging mutations in Homologous - DNA repair (HDR) genes or
      mutations such as ATM, CHK2, MRN (MRE11/NBS1/RAD50), CDKN2A/B and APOBEC will be treated with
      olaparib or olaparib and AZD6738. Enrollment to the olaparib monotherapy arm will be
      completed prior to commencement of enrollment to the olaparib and AZD6738 arm. Patients with
      tumors harboring IDH1/IDH2 mutations will be treated with olaparib. Patients with tumors
      harboring either TP53 or KRAS mutations or mutations in KRAS and TP53 will be treated with
      AZD1775 plus olaparib. Patients with tumors harboring PTEN, PIK3CA, AKT, or ARID1A mutations
      or other molecular aberrations leading to dysregulation of the PI3K/AKT pathway will be
      treated with AZD5363 plus olaparib.
    

Trial Arms

NameTypeDescriptionInterventions
Group 1ExperimentalPatients with cholangiocarcinoma harboring IDH 1/2 tumors will be treated with olaparib. Patients with tumors harboring mutation in HDR genes will be treated with olaparib.
  • AZD2281
Group 2ExperimentalPatients with tumors harboring PTEN, PIK3CA, AKT, or ARID1A mutations or other molecular aberrations leading to dysregulation of the PI3K/AKT pathway will be treated with AZD5363 plus olaparib.
  • AZD2281
  • AZD5363
Group 3ExperimentalPatients with tumors harboring either TP53 or KRAS mutations or mutations in KRAS and TP53 will be treated with AZD1775 plus olaparib. TP53 mutations must be found on the TP53 mutation eligibility list.
  • AZD2281
  • AZD1775
Group 4ExperimentalPatients with tumors harboring mutations in HDR genes, including ATM, CHK2, APOBEC, MRE11 complex, will be treated with AZD6738 and olaparib.
  • AZD2281
  • AZD6738

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically documented metastatic cancer (solid tumors, not including hematologic
             malignancies)

          -  Patients who have received standard first-line therapy for metastatic cancer (except
             for the tumors for which no first-line therapy exists) and in whom a trial of targeted
             therapy is considered the best available treatment option. Eligible patients should
             not have available therapies that will convey clinical benefit.

          -  Progressive cancer at the time of study entry

          -  Measurable disease by RECIST v1.1

          -  Age ≥ 18 years

          -  Life expectancy ≥ 16 weeks

          -  Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1
             (APPENDIX A: Performance Status Criteria)

          -  Able to understand the nature of this trial and provide written informed consent

          -  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.

          -  Molecular testing or appropriate IHC results from CLIA-certified laboratories used for
             patient eligibility should be obtained from the most recent tumor biopsy (baseline
             tumor biopsies and on-progression tumor biopsies are optional)

          -  Prior treatment with PARP inhibitor monotherapy is allowed in the combination arms.

          -  Prior radiation therapy is allowed. Patients must not have received radiation therapy
             within 21 days prior to the initiation of study treatment.

          -  Other therapies: Prior experimental (non-FDA approved) therapies and immunotherapies
             are allowed. Patients must not have received these therapies for 21 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 clinically significant effects of these
             therapies.

          -  Adequate hematologic function defined as:

               -  Absolute neutrophil count (ANC) ≥ 1500/μL

               -  White blood cells (WBC) > 3x109/L

               -  Hemoglobin (Hgb) ≥ 10 g/dL (may be achieved with erythropoietin agents; no blood
                  transfusions in the 28 days prior to entry)

               -  Platelets ≥ 100,000/μL

               -  No features suggestive of MDS/AML on peripheral blood smear

          -  Adequate renal and liver function defined as:

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × the
                  upper limit of normal (ULN) (≤ 5 × ULN if considered due to primary or metastatic
                  liver involvement)

               -  Total bilirubin ≤ 1.5 ×ULN

               -  Alkaline phosphatase ≤ 2× ULN (≤ 5 × ULN if considered due to tumor)

               -  Serum creatinine ≤ 1.5 ULN

          -  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/plain x-ray/clinical exam at
             baseline and follow up visits.

          -  Women of child-bearing potential must have a negative pregnancy test (urine or serum)
             within 28 days prior to starting the study drug. Both males and females must agree to
             adequate birth control if conception is possible during the study and for 6 months
             after the last dose. Female patients are considered to not be of child-bearing
             potential if they have a history of tubal ligation or hysterectomy or are
             post-menopausal with a minimum of 1 year without menses.

        Exclusion Criteria:

          -  Patients with known germline BRCA mutations in breast cancers will be excluded from
             the study, however testing is not required for inclusion in the study.

          -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
             staff and/or staff at the study site)

          -  Prior standard of care cancer chemotherapy, immunotherapy, or radiotherapy <21 days
             prior to first dose of study agent(s)

          -  Patients with hematologic malignancies (includes patients with myelodysplastic
             syndrome/acute myeloid leukemia).

          -  Patients with primary CNS malignancies

          -  Patients must not have received allogeneic stem cell transplant

          -  Concurrent administration of any other anti-cancer therapy

               -  Bisphosphonates and Denosumab for bone metastases are allowed if started at least
                  4 weeks prior to treatment with study agent(s).

               -  Octreotide is allowed if dose is stable for >3 months with no worsening of
                  carcinoid syndrome

               -  Hormonal therapy with luteinizing hormone-releasing hormone (LHRH) analogues for
                  medical castration in patients with castrate-resistant prostate cancer is
                  permitted

          -  Patients who have not demonstrated stable recover (28 days or greater) from ≤ CTCAE
             grade 2 non-hematological toxicities related to prior therapy such as peripheral
             neuropathy or alopecia, or incomplete recovery from previous surgery, unless agreed by
             the Principal Investigator (PI) and documented are not eligible to participate in this
             study.

          -  Active or untreated brain metastases or spinal cord compression

               -  A scan to confirm the absence of brain metastases is not required.

               -  Patients with treated brain metastases or spinal cord compression are eligible if
                  they have minimal neurologic symptoms and evidence of stable disease (for at
                  least 1 month) or response on follow-up scan. The patient can receive a stable
                  dose of corticosteroids before and during the study if started at least 28 days
                  prior to initiating the study agent(s)..

          -  History of carcinomatous meningitis

          -  Patients with second primary cancer, except: adequately treated non-melanoma skin
             cancer, curatively treated stage I cancers (cervix, breast, colon, lung, or prostate
             as examples) or other advanced (> Stage I)solid tumors curatively treated with no
             evidence of disease for ≥ 5 years.

          -  Patient must not have a co-morbid condition(s) that, in the opinion of the
             investigator, prevent safe treatment.

          -  Immunocompromised patients, e.g., patients who are known to be serologically positive
             for human immunodeficiency virus (HIV) and are receiving antiviral therapy (testing is
             not part of the protocol).

             - Patients with known (testing is not part of the protocol) active hepatic disease
             (i.e., Hepatitis B or C) due to risk of drug interactions with anti-viral therapy.

          -  Any of the following cardiovascular events within 6 months prior to study entry:
             myocardial infarction, malignant hypertension, severe/unstable angina, symptomatic
             congestive heart failure, cerebral vascular accident, or transient ischemic attack

          -  History or presence of clinically significant ventricular or atrial dysrhythmia >
             Grade 2 (NCI CTCAE v4.0)

             − Patients with chronic, rate-controlled atrial arrhythmias who do not have other
             cardiac abnormalities are eligible.

          -  Major surgery within 3 weeks prior to first dose of study treatment, and patients must
             have recovered from the effects of surgery

          -  Patients unable to swallow orally administered medication and patients with
             gastrointestinal disorders likely to interfere with absorption of the study medication

          -  Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory
             bowel disease) or significant bowel resection that would preclude adequate absorption

          -  Patients with uncontrolled seizures

          -  Inadequate bone marrow reserve within past 28 days prior to study treatment as
             demonstrated by:

               -  Absolute neutrophil count (ANC) < 1500/μl,

               -  WBC ≤ 3x109/L

               -  Platelet count (PLT) < 100,000/μl, or

               -  Hemoglobin (Hgb) < 10 g/dL

          -  Blood (packed red blood cells, platelets) transfusions within 1 month prior to study
             start

          -  Whole blood transfusion in the last 120 days prior to entry to the study

          -  Patients with concomitant use of drugs, herbal supplements and/or ingestion of foods
             known to strongly modulate CYP3A4 enzyme activity as specified in the drug specific
             appendix.

          -  Women who are pregnant or lactating (breastfeeding)

          -  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

          -  Any other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that may increase the risk associated with study participation or may
             interfere with the interpretation of study results

             − 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, superior vena
             cava syndrome, extensive bilateral lung disease on HRCT scan or any psychiatric
             disorder that prohibits obtaining informed consent

          -  Psychological, familial, sociological, or geographical conditions that do not permit
             compliance with the protocol
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:Change from baseline to 16 weeks
Safety Issue:
Description:Tumor overall response rate (ORR) in molecularly selected patients with measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), before versus after 16 weeks of treatment across tumor types in each arm of the study (Note: there will be no formal comparison between arms)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Joseph Paul Eder

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