Neoplasms

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Rare Diseases

Pheochromocytoma

Paraganglioma

Carcinoma, Neuroendocrine

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Paragangliomas 1

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Temozolomide

Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Enzyme Inhibitors

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. 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 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.

Biospecimen Collection

Computed Tomography with Contrast

Magnetic Resonance Imaging

Quality-of-Life Assessment

Site Public Contact

Bryan A. Faller

Chih-Yi Liao

Vamsi K. Vasireddy

Jaydira Del Rivero

Kimberly J. Perez

Elie G. Dib

Daniel M. Anderson

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.

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.

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

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

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.

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.

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.

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.

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.

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.

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.

National Cancer Institute (NCI)

Lanreotide

Patients with a histopathologically confirmed diagnosis of malignant paraganglioma or pheochromocytoma and either evidence of metastases or unresectability who meet the inclusion/exclusion criteria. Approximately 40 patients will be enrolled.

Participants will receive lanreotide 120 mg deep subcutaneous injection every 4 weeks (±7 days) for 52 weeks, followed by an extension phase in which all patients will continue to receive lanreotide 120 mg injection every 4 weeks (±7 days) if there is no evidence of disease progression.

Research Nurse Navigator

Antonio Fojo, MD, PhD

Bahar Laderian, MD

The objectives of this study are:

* To assess the efficacy of lanreotide given every 4 weeks in participants with advanced or metastatic paraganglioma/ pheochromocytoma.
* To assess the toxicity and safety of lanreotide in participants with advanced or metastatic paraganglioma/ pheochromocytoma.
* To document the effects of lanreotide on markers of biochemical activity in participants with advanced or metastatic paraganglioma/ pheochromocytoma.

Primary endpoints:

• Assess efficacy by estimating the tumor growth rate while a patient is enrolled on study and comparing the growth rates on lanreotide to the pre-enrolment growth rate.

Secondary endpoints include measurement of:

* Overall survival (OS)
* Progression-free survival (PFS)
* Overall response rate (ORR) according to RECIST defined as partial response (PR) + complete response (CR)
* Magnitude of reduction in levels of 24-hour urinary metanephrines, catecholamines and magnitude of reduction in serum chromogranin A, evaluated every two months while enrolled on study.

Lanreotide is FDA approved for certain kinds of neuroendocrine tumors. This study seeks to determine if lanreotide is beneficial for patients with paraganglioma/ pheochromocytoma.

Given the rarity of pheochromocytoma/paraganglioma that precludes the conduct of a randomized clinical trial in a timely manner, a novel method for assessing efficacy is being proposed. Efficacy will be assessed by estimating the tumor growth rate while a patient is enrolled on study and comparing the growth rates on lanreotide to the pre-enrollment growth rates. The method of analysis that will be used has been previously described. For this assessment a minimum of three tumor measurements will be required.

LAnreotide in Metastatic Pheochromocytoma / PARAganglioma (LAMPARA)

Exploratory Phase II Study of LAnreotide in Metastatic Pheochromocytoma/PARAganglioma (LAMPARA)

Efficacy will be assessed by measuring the tumor growth rate while a patient is enrolled on study and comparing the growth rates on lanreotide to the pre-enrollment growth rates. Tumor growth measured by a CT or MRI scan in pre-treatment, and minimum of three scans (prior to every 3rd visit, or every 12 weeks) in post-treatment.

The length of time from the start of treatment that subjects with the disease are still alive.

ORR is defined as the proportion of the subjects in the analysis population who have a complete response (CR) or partial response (PR). Responses are based on assessments per RECIST 1.1. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST criteria.

* Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have change in short axis to less than 10 mm.
* Partial Response (PR): At least a 30% change in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

PFS is defined as the time from the first day of treatment to the first documented disease progression per RECIST 1.1 criteria and the Kaplan-Meier curve. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST criteria.

Biochemical response of greater than 20% change in 24-hour urinary metanephrines, catecholamines and serum chromogranin A levels compared to baseline, sustained for \>12-week-period. Evaluated every two months while enrolled on study, although levels may be obtained as frequently as the investigator desires.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Testing the Addition of an Anticancer Drug, Olaparib, to the Usual Chemotherapy (Temozolomide) for Advanced Neuroendocrine Cancer	NCT04394858	Advanced Adrena... Advanced Paraga... Metastatic Adre... Metastatic Para... Stage III Adren... Stage IV Adrena... Unresectable Ad... Unresectable Pa...	Biospecimen Col... Computed Tomogr... Magnetic Resona... Olaparib Quality-of-Life... Temozolomide	18 Years -	National Cancer Institute (NCI)
LAnreotide in Metastatic Pheochromocytoma / PARAganglioma (LAMPARA)	NCT03946527	Paraganglioma Pheochromocytom...	Lanreotide	18 Years -	Columbia University
Testing the Addition of an Anticancer Drug, Olaparib, to the Usual Chemotherapy (Temozolomide) for Advanced Neuroendocrine Cancer	NCT04394858	Advanced Adrena... Advanced Paraga... Metastatic Adre... Metastatic Para... Stage III Adren... Stage IV Adrena... Unresectable Ad... Unresectable Pa...	Biospecimen Col... Computed Tomogr... Magnetic Resona... Olaparib Quality-of-Life... Temozolomide	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for advanced paraganglioma