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

Metastatic Adrenal Gland Pheochromocytoma Clinical Trial

Official title:

A Prospective, Multi-Institutional Phase II Trial Evaluating Temozolomide vs. Temozolomide and Olaparib for Advanced Pheochromocytoma and Paraganglioma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04394858
• Other study ID #: NCI-2020-03379
• Secondary ID: NCI-2020-03379A0
• Status: Recruiting
• Phase: Phase 2
• Start date: March 17, 2021
• Est. completion date: February 28, 2025

Study information

• Verified date: January 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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 from where it first started (primary site) to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Poly (adenosine diphosphate [ADP]-ribose) polymerases (PARPs) are proteins that help repair deoxyribonucleic acid (DNA) mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Chemotherapy drugs, 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.

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. Patients undergo computed tomography (CT) with contrast or magnetic resonance imaging (MRI) throughout the study and undergo mandatory collection of blood samples prior to treatment. Patients may optionally undergo collection of blood samples at the time of progression.

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 undergo CT with contrast or MRI throughout the study and undergo mandatory collection of blood samples prior to treatment. Patients may optionally undergo collection of blood samples at the time of progression.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 76
• Est. completion date: February 28, 2025
• Est. primary completion date: February 28, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 CT or 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 somatostatin analog, 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

• 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

• 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)

• 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 if prior radionuclide therapy Hemoglobin >= 8 mg/dL if no prior radionuclide therapy

• In the absence of transfusion within the previous 24 hours. Radionuclide therapy includes PRRT or MIBG

• 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

• No indication of uncontrolled, potentially reversible cardiac condition(s) as determined by investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, Fridericia's formula-corrected QT interval [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

• 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 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

Related Conditions & MeSH terms

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

Intervention

Procedure:
• Biospecimen Collection
Undergo collection of blood samples
• Computed Tomography with Contrast
Undergo CT with contrast
• Magnetic Resonance Imaging
Undergo MRI

Drug:
• Olaparib
Given PO

Other:
• Quality-of-Life Assessment
Ancillary studies

Drug:
• Temozolomide
Given PO

Locations

Country	Name	City	State
United States	Providence Regional Cancer System-Aberdeen	Aberdeen	Washington
United States	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania
United States	Alaska Breast Care and Surgery LLC	Anchorage	Alaska
United States	Alaska Oncology and Hematology LLC	Anchorage	Alaska
United States	Alaska Women's Cancer Care	Anchorage	Alaska
United States	Anchorage Associates in Radiation Medicine	Anchorage	Alaska
United States	Anchorage Oncology Centre	Anchorage	Alaska
United States	Anchorage Radiation Therapy Center	Anchorage	Alaska
United States	Katmai Oncology Group	Anchorage	Alaska
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	Trinity Health Saint Joseph Mercy Hospital Ann Arbor	Ann Arbor	Michigan
United States	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey
United States	PeaceHealth Saint Joseph Medical Center	Bellingham	Washington
United States	Saint Charles Health System	Bend	Oregon
United States	National Institutes of Health Clinical Center	Bethesda	Maryland
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Trinity Health Medical Center - Brighton	Brighton	Michigan
United States	Providence Saint Joseph Medical Center/Disney Family Cancer Center	Burbank	California
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Minnesota Oncology - Burnsville	Burnsville	Minnesota
United States	Cambridge Medical Center	Cambridge	Minnesota
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Trinity Health Medical Center - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Caro Cancer Center	Caro	Michigan
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Centralia Oncology Clinic	Centralia	Illinois
United States	Providence Regional Cancer System-Centralia	Centralia	Washington
United States	Chelsea Hospital	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Clackamas Radiation Oncology Center	Clackamas	Oregon
United States	Providence Cancer Institute Clackamas Clinic	Clackamas	Oregon
United States	Hematology Oncology Consultants-Clarkston	Clarkston	Michigan
United States	Newland Medical Associates-Clarkston	Clarkston	Michigan
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Memorial Sloan Kettering Commack	Commack	New York
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	Bay Area Hospital	Coos Bay	Oregon
United States	Carle at The Riverfront	Danville	Illinois
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Ascension Saint John Hospital	Detroit	Michigan
United States	Illinois CancerCare-Dixon	Dixon	Illinois
United States	Great Lakes Cancer Management Specialists-Doctors Park	East China Township	Michigan
United States	Pocono Medical Center	East Stroudsburg	Pennsylvania
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	Swedish Cancer Institute-Edmonds	Edmonds	Washington
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	Providence Regional Cancer Partnership	Everett	Washington
United States	Farmington Health Center	Farmington	Utah
United States	Genesee Cancer and Blood Disease Treatment Center	Flint	Michigan
United States	Genesee Hematology Oncology PC	Flint	Michigan
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Holy Cross Hospital	Fort Lauderdale	Florida
United States	Unity Hospital	Fridley	Minnesota
United States	Saint Luke's Cancer Institute - Fruitland	Fruitland	Idaho
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Academic Hematology Oncology Specialists	Grosse Pointe Woods	Michigan
United States	Great Lakes Cancer Management Specialists-Van Elslander Cancer Center	Grosse Pointe Woods	Michigan
United States	Michigan Breast Specialists-Grosse Pointe Woods	Grosse Pointe Woods	Michigan
United States	Memorial Sloan Kettering Westchester	Harrison	New York
United States	Lehigh Valley Hospital-Hazleton	Hazleton	Pennsylvania
United States	Swedish Cancer Institute-Issaquah	Issaquah	Washington
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	Kadlec Clinic Hematology and Oncology	Kennewick	Washington
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	Providence Regional Cancer System-Lacey	Lacey	Washington
United States	University of Michigan Health - Sparrow Lansing	Lansing	Michigan
United States	Cancer Centers of Southwest Oklahoma Research	Lawton	Oklahoma
United States	Hope Cancer Clinic	Livonia	Michigan
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	PeaceHealth Saint John Medical Center	Longview	Washington
United States	Great Lakes Cancer Management Specialists-Macomb Medical Campus	Macomb	Michigan
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	Michigan Breast Specialists-Macomb Township	Macomb	Michigan
United States	Fairview Clinics and Surgery Center Maple Grove	Maple Grove	Minnesota
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Saint John's Hospital - Healtheast	Maplewood	Minnesota
United States	Saint Mary's Oncology/Hematology Associates of Marlette	Marlette	Michigan
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Saint Luke's Cancer Institute - Meridian	Meridian	Idaho
United States	Memorial Sloan Kettering Monmouth	Middletown	New Jersey
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Health Partners Inc	Minneapolis	Minnesota
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Saint Patrick Hospital - Community Hospital	Missoula	Montana
United States	Monticello Cancer Center	Monticello	Minnesota
United States	Memorial Sloan Kettering Bergen	Montvale	New Jersey
United States	Saint Luke's Cancer Institute - Nampa	Nampa	Idaho
United States	UC Comprehensive Cancer Center at Silver Cross	New Lenox	Illinois
United States	Cancer Center of Western Wisconsin	New Richmond	Wisconsin
United States	New Ulm Medical Center	New Ulm	Minnesota
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Providence Newberg Medical Center	Newberg	Oregon
United States	Dana-Farber Cancer Institute - Chestnut Hill	Newton	Massachusetts
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Providence Willamette Falls Medical Center	Oregon City	Oregon
United States	University of Chicago Medicine-Orland Park	Orland Park	Illinois
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Hope Cancer Center	Pontiac	Michigan
United States	Michigan Healthcare Professionals Pontiac	Pontiac	Michigan
United States	Newland Medical Associates-Pontiac	Pontiac	Michigan
United States	Trinity Health Saint Joseph Mercy Oakland Hospital	Pontiac	Michigan
United States	Oregon Health and Science University	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Fairview Northland Medical Center	Princeton	Minnesota
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Saint Charles Health System-Redmond	Redmond	Oregon
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Great Lakes Cancer Management Specialists-Rochester Hills	Rochester Hills	Michigan
United States	Ascension Saint Mary's Hospital	Saginaw	Michigan
United States	Oncology Hematology Associates of Saginaw Valley PC	Saginaw	Michigan
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	University of Utah Sugarhouse Health Center	Salt Lake City	Utah
United States	Pacific Gynecology Specialists	Seattle	Washington
United States	Swedish Medical Center-Ballard Campus	Seattle	Washington
United States	Swedish Medical Center-Cherry Hill	Seattle	Washington
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	PeaceHealth United General Medical Center	Sedro-Woolley	Washington
United States	Saint Francis Regional Medical Center	Shakopee	Minnesota
United States	Providence Regional Cancer System-Shelton	Shelton	Washington
United States	Bhadresh Nayak MD PC-Sterling Heights	Sterling Heights	Michigan
United States	Lakeview Hospital	Stillwater	Minnesota
United States	Ascension Saint Joseph Hospital	Tawas City	Michigan
United States	Saint Luke's Cancer Institute - Twin Falls	Twin Falls	Idaho
United States	Memorial Sloan Kettering Nassau	Uniondale	New York
United States	Carle Cancer Center	Urbana	Illinois
United States	PeaceHealth Southwest Medical Center	Vancouver	Washington
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	Providence Saint Mary Regional Cancer Center	Walla Walla	Washington
United States	Advanced Breast Care Center PLLC	Warren	Michigan
United States	Great Lakes Cancer Management Specialists-Macomb Professional Building	Warren	Michigan
United States	Macomb Hematology Oncology PC	Warren	Michigan
United States	Michigan Breast Specialists-Warren	Warren	Michigan
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	Illinois CancerCare - Washington	Washington	Illinois
United States	Saint Mary's Oncology/Hematology Associates of West Branch	West Branch	Michigan
United States	Rice Memorial Hospital	Willmar	Minnesota
United States	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota
United States	Fairview Lakes Medical Center	Wyoming	Minnesota
United States	Providence Regional Cancer System-Yelm	Yelm	Washington
United States	Huron Gastroenterology PC	Ypsilanti	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Biochemical response	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.	Up to 5 years
Other	Biomolecular markers associated with clinical outcome	Will analyze for methyltransferase (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.	Up to 5 years
Primary	Progression-free survival (PFS)	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.	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
Secondary	Overall survival (OS)	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.	From randomization to death due to any cause, assessed up to 5 years
Secondary	Objective response	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.	Up to 5 years
Secondary	Incidence of adverse events	Will be assessed per National Cancer Institute 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.	Up to 5 years