Testing the Addition of an Anticancer Drug, Olaparib, to the Usual Chemotherapy (Temozolomide) for Advanced Neuroendocrine Cancer
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|ClinicalTrials.gov Identifier: NCT04394858|
Recruitment Status : Recruiting
First Posted : May 20, 2020
Last Update Posted : March 3, 2023
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|Condition or disease||Intervention/treatment||Phase|
|Advanced Adrenal Gland Pheochromocytoma Advanced Paraganglioma Metastatic Adrenal Gland Pheochromocytoma Metastatic Paraganglioma Unresectable Adrenal Gland Pheochromocytoma Unresectable Paraganglioma||Drug: Olaparib Other: Quality-of-Life Assessment Drug: Temozolomide||Phase 2|
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.
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.
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.
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||76 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Prospective, Multi-Institutional Phase II Trial Evaluating Temozolomide vs. Temozolomide and Olaparib for Advanced Pheochromocytoma and Paraganglioma|
|Actual Study Start Date :||November 2, 2020|
|Estimated Primary Completion Date :||February 29, 2024|
|Estimated Study Completion Date :||February 29, 2024|
Experimental: Arm I (temozolomide, olaparib)
Patients 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.
Other: Quality-of-Life Assessment
Other Name: Quality of Life Assessment
Active Comparator: Arm II (temozolomide)
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.
Other: Quality-of-Life Assessment
Other Name: Quality of Life Assessment
- 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 ]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.
- Overall survival (OS) [ Time Frame: From randomization to death due to any cause, assessed up to 5 years ]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.
- Objective response [ Time Frame: Up to 5 years ]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.
- Incidence of adverse events [ Time Frame: Up to 5 years ]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.
- Biochemical response [ Time Frame: Up to 5 years ]Levels of chromogranin A, urine and/or plasma catecholamines and metanephrines may predict response to therapy. The proportion of patients with a biochemical response of partial response or better, as determined by plasma and/or urine catecholamines and metanephrines, will be calculated, and a 95% confidence interval will be placed on this proportion. For each factor, we will calculate the mean +/- standard deviation, minimum, maximum, and quartiles; in addition, we will generate box and whisker plot.
- Biomolecular markers associated with clinical outcome [ Time Frame: Up to 5 years ]Will analyze for MGMT methylation expression in archival tumors and correlate with the radiographic response rate in metastatic pheochromocytoma/paraganglioma. This is hypothesis generated box and whisker plot.
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
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
- 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
- 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)
- Age >= 18 years
- 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
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04394858
|Principal Investigator:||Jaydira Del Rivero||Alliance for Clinical Trials in Oncology|
|Responsible Party:||National Cancer Institute (NCI)|
|Other Study ID Numbers:||
NCI-2020-03379 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
A021804 ( Other Identifier: Alliance for Clinical Trials in Oncology )
A021804 ( Other Identifier: CTEP )
U10CA180821 ( U.S. NIH Grant/Contract )
|First Posted:||May 20, 2020 Key Record Dates|
|Last Update Posted:||March 3, 2023|
|Last Verified:||March 2023|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
|Plan Description:||NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Poly(ADP-ribose) Polymerase Inhibitors
Antineoplastic Agents, Alkylating
Molecular Mechanisms of Pharmacological Action