Clinical Trials /

Testing the Addition of an Anticancer Drug, Olaparib, to the Usual Chemotherapy (Temozolomide) for Advanced Neuroendocrine Cancer

NCT04394858

Description:

This phase II trial studies how well the addition of olaparib to the usual treatment, temozolomide, works in treating patients with neuroendocrine cancer (pheochromocytoma or paraganglioma) that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving olaparib with temozolomide may shrink or stabilize the cancer in patients with pheochromocytoma or paraganglioma better than temozolomide alone.

Related Conditions:
  • Adrenal Gland Pheochromocytoma
  • Paraganglioma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of an Anticancer Drug, Olaparib, to the Usual Chemotherapy (Temozolomide) for Advanced Neuroendocrine Cancer
  • Official Title: A Prospective, Multi-Institutional Phase II Trial Evaluating Temozolomide vs. Temozolomide and Olaparib for Advanced Pheochromocytoma and Paraganglioma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-03379
  • SECONDARY ID: NCI-2020-03379
  • SECONDARY ID: A021804
  • SECONDARY ID: A021804
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT04394858

Conditions

  • Advanced Adrenal Gland Pheochromocytoma
  • Advanced Paraganglioma
  • Metastatic Adrenal Gland Pheochromocytoma
  • Metastatic Paraganglioma
  • Unresectable Adrenal Gland Pheochromocytoma
  • Unresectable Paraganglioma

Interventions

DrugSynonymsArms
OlaparibAZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Arm I (temozolomide, olaparib)
TemozolomideCCRG-81045, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831, Methazolastone, RP-46161, SCH 52365, Temcad, Temodal, Temodar, Temomedac, TMZArm I (temozolomide, olaparib)

Purpose

This phase II trial studies how well the addition of olaparib to the usual treatment, temozolomide, works in treating patients with neuroendocrine cancer (pheochromocytoma or paraganglioma) that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving olaparib with temozolomide may shrink or stabilize the cancer in patients with pheochromocytoma or paraganglioma better than temozolomide alone.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To compare the progression-free survival (PFS) of patients with advanced pheochromocytoma
      and paraganglioma (APP) receiving temozolomide (dose dense) and olaparib to that of patients
      receiving temozolomide (pulse dose) alone.

      SECONDARY OBJECTIVES:

      I. To compare the overall survival (OS) of patients with APP receiving temozolomide (dose
      dense) and olaparib versus (vs.) temozolomide (pulse dose) alone.

      II. To compare the objective response rate (ORR) associated with temozolomide (dose dense)
      and olaparib vs. temozolomide (pulse dose) alone in patients with APP.

      III. To evaluate and compare the toxicity profile of temozolomide-based combinations
      (temozolomide [dose dense] and olaparib vs. temozolomide [pulse dose]) in patients with APP
      using Common Terminology Criteria for Adverse Events (CTCAE) and Patient-Reported Outcomes
      (PRO)-CTCAE.

      OTHER OBJECTIVE:

      I. Results of the primary analysis will be examined for consistency, while taking into
      account the stratification factors and/or covariates of baseline quality of life (QOL) and
      fatigue.

      EXPLORATORY OBJECTIVES:

      I. To assess biochemical response: serum catecholamines and metanephrines; urine
      catecholamines and metanephrines.

      II. To assess biomolecular markers associated with clinical outcome: germline succinyl
      dehydrogenase (SDH) mutations and tumor status of the repair enzyme
      methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT).

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive temozolomide orally (PO) once daily (QD) and olaparib PO twice daily
      (BID) on days 1-7. Treatment with temozolomide repeats every 21 days for up to 13 cycles in
      the absence of disease progression or unacceptable toxicity. Cycles of olaparib repeat every
      21 days in the absence of disease progression or unacceptable toxicity.

      ARM II: Patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for
      up to 13 cycles in the absence of disease progression or unacceptable toxicity.

      Patients discontinuing treatment due to reasons other than disease progression are followed
      every 8 weeks until disease progression, then every 6 months until 5 years after start of
      treatment. Patients discontinuing treatment due to disease progression are followed every 6
      months for 5 years after start of treatment.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (temozolomide, olaparib)ExperimentalPatients receive temozolomide PO QD and olaparib PO BID on days 1-7. Treatment with temozolomide repeats every 21 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. Cycles of olaparib repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Olaparib
  • Temozolomide
Arm II (temozolomide)Active ComparatorPatients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity.
  • Temozolomide

Eligibility Criteria

        Inclusion Criteria:

          -  Documentation of disease

               -  Histologic documentation: Histologically-proven advanced (metastatic or
                  unresectable primary) pheochromocytoma or paraganglioma

               -  Stage: Advanced (metastatic or unresectable primary) disease

               -  Tumor site: Histologically-proven pheochromocytoma or paraganglioma

               -  Radiographic evaluation: Radiographic evidence of disease progression by Response
                  Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 in the 12 months
                  prior to registration

          -  Measurable disease

               -  Lesions must be accurately measured in at least one dimension (longest diameter
                  to be recorded) as >= 1 cm with computed tomography (CT) or magnetic resonance
                  imaging (MRI) (or >= 1.5 cm for lymph nodes). Non-measurable disease includes
                  disease smaller than these dimensions or lesions considered truly non-measurable
                  including: leptomeningeal disease, ascites, pleural or pericardial effusion,
                  lymphangitic involvement of skin or lung

          -  Prior treatment with other chemotherapy, radiotherapy (including peptide radionuclide
             receptor therapy [PRRT]), or surgery must be completed >= 28 days prior to
             registration. Patients must have recovered from any effects of any major surgery prior
             to registration

          -  Prior treatment with radiolabeled metaiodobenzylguanidine (MIBG) must be completed >=
             12 weeks prior to registration and lifetime cumulative 131I-MIBG dose must be < 1000
             MBq kg-1 (36 mCi kg-1)

          -  Prior treatment with antibiotics must be completed >= 7 days prior to registration

          -  Contraception

               -  Therapy utilized in this trial is associated with medium/high fetal risk

               -  Women of childbearing potential and their partners, who are sexually active, must
                  agree to use two highly effective forms of contraception in combination. This
                  should be started from the time of registration and continue throughout the
                  period of taking study treatment and for at least 1 month after last dose of
                  study drug(s), or they must totally/truly abstain from any form of sexual
                  intercourse

               -  Male patients must use a condom during treatment and for 3 months after the last
                  dose of study drug(s) when having sexual intercourse with a pregnant woman or
                  with a woman of childbearing potential. Female partners of male patients should
                  also use a highly effective form of contraception if they are of childbearing
                  potential. Male patients should not donate sperm throughout the period of taking
                  study drug(s) and for 3 months following the last dose of study drug(s)

          -  Eastern Cooperative Oncology Group (ECOG) performance status: 0-2

          -  Absolute neutrophil count >= 1,500/mm^3

          -  Platelet count >= 100,000/mm^3

          -  Hemoglobin >= 10 mg/dL

               -  In the absence of transfusion within the previous 24 hours

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN)

               -  Except in the case of Gilbert's syndrome, then total bilirubin must be =< 3.0 x
                  ULN

          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x ULN

          -  Creatinine < 1.5 x ULN OR calculated (calc.) creatinine clearance > 50 mL/min

               -  Calculated by Cockcroft-Gault equation

          -  Patients with human immunodeficiency virus (HIV) positivity are allowed if CD4 count >
             250 cells/uL and they have an undetectable HIV viral load within 6 months of
             registration

        Exclusion Criteria:

          -  No prior treatment with temozolomide, dacarbazine, or a poly ADP ribose polymerase
             (PARP) inhibitor

          -  No prior allogeneic bone marrow transplant or double umbilical cord blood
             transplantation (dUCBT)

          -  Not pregnant and not nursing, because this study involves an agent that has known
             genotoxic, mutagenic, and teratogenic effects. Therefore, for women of childbearing
             potential only, a negative pregnancy test done =< 7 days prior to registration is
             required

          -  No indication of uncontrolled, potentially reversible cardiac condition(s) as
             determined by investigator (e.g., unstable ischemia, uncontrolled symptomatic
             arrhythmia, congestive heart failure, QTcF prolongation > 500 msec, electrolyte
             disturbances, etc.) and no known congenital long QT syndrome

          -  No extensive bilateral lung disease or pneumonitis

          -  No abnormal organ or bone marrow function =< 28 days prior to registration

          -  No active infection

          -  No history of myelodysplastic syndrome (MDS) (or any dysplastic leukocyte morphology
             suggestive of MDS) or acute myeloid leukemia

          -  No known gastrointestinal condition(s) that might predispose for drug intolerability
             or poor drug absorption

          -  No known medical condition causing an inability to swallow oral formulations of agents

          -  No history of allergic reaction attributed to compounds of similar chemical or
             biologic composition to PARP inhibitors

          -  Concurrent use of combination antiretroviral therapy (ART) is not permitted

          -  Chronic concomitant treatment with strong or moderate CYP3A4 inducers or inhibitors is
             not allowed. Patients must discontinue the agent(s) >= 21 days prior to registration;
             enzalutamide and/or phenobarbital must be discontinued >= 5 weeks prior to
             registration
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From randomization to the first documentation of disease progression (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) or death, assessed up to 5 years
Safety Issue:
Description:Will be compared between treatment arms using the un-stratified log-rank test at one-sided level of 0.11 and the p-value will be used for decision making. The hazard ratio will be estimated using a Cox proportional hazards model and the 95% confidence interval for the hazard ratio will be provided. Results from a stratified analysis will also be provided. Kaplan-Meier methodology will be used to estimate the median PFS for each treatment arm, and Kaplan-Meier curves will be produced. Brookmeyer-Crowley methodology will be used to construct the 95% confidence interval for the median PFS for each treatment arm.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:From randomization to death due to any cause, assessed up to 5 years
Safety Issue:
Description:Patients who are alive will be censored at last follow-up. The distribution of survival time will be estimated using the method of Kaplan-Meier. OS will be compared between treatment arms using the log-rank test. OS medians, survival rates and hazard ratio will be estimated along with 95% confidence intervals.
Measure:Objective response
Time Frame:Up to 5 years
Safety Issue:
Description:Will be assessed by RECIST version 1.1 criteria. Will be estimated using objective response rate where objective response rate is defined as the number of evaluable patients achieving a response (partial response or complete response per RECIST version 1.1) during treatment with study therapy divided by the total number of evaluable patients. Rates of response will be compared across arms using a Chi-Square Test for Proportion. Point estimates will be generated for objective response rates within each arm along with 95% binomial confidence intervals.
Measure:Incidence of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description:Will be assessed per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The term toxicity is defined as adverse events that are classified as possibly, probably, or definitely related to study treatment. Toxicities will be evaluated via the ordinal Common Terminology Criteria for Adverse Events standard toxicity grading. Similarly, scores (0-4) and the maximum score for each Patient-Reported Outcomes-CTCAE item will be recorded for each patient.

Details

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

Last Updated

December 24, 2020