Neoplasms

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Multiple Endocrine Neoplasia Type 1

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Neoplasms by Histologic Type

Disease Attributes

Endocrine System Diseases

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Adrenal Cortex Neoplasms

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Adrenal Cortex Diseases

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Neuroendocrine Tumor

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Merkel Cell Carcinoma

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Functioning Pancreatic Endocrine Tumor

VIPoma

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Paragangliomas 1

Pancreatic Cancer

Antineoplastic Agents

All Drugs and Chemicals

Capecitabine

Temozolomide

Veliparib

Antimetabolites

Antineoplastic Agents, Alkylating

Alkylating Agents

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Capecitabine PO BID on days 1-14, temozolomide PO BID on days 10-14 and veliparib PO BID on days 10-14.

Pharmacological Study

Laboratory Biomarker Analysis

Jordan Berlin, M.D.

This phase I trial studies the side effects and best dose of veliparib when given together with capecitabine and temozolomide in treating patients with neuroendocrine tumor that has spread to other places in the body and usually cannot be cured or controlled with treatment, has returned after a period of improvement, and cannot be removed by surgery. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as capecitabine and 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.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of veliparib (ABT-888) in combination with capecitabine and temozolomide in patients with advanced well-differentiated neuroendocrine tumors.

SECONDARY OBJECTIVES:

2. To determine the safety profile of the combination of capecitabine, temozolomide and veliparib in patients with advanced well-differentiated neuroendocrine tumors (NET).

3. To evaluate the antitumor activity of the combination of capecitabine, temozolomide and veliparib in advanced well-differentiated NET patients

4. To determine progression-free survival (PFS) of the combination of capecitabine, temozolomide, and veliparib in advanced well-differentiated NET patients IV. To evaluate the association between pharmacodynamic biomarkers and response in patients with advanced well-differentiated NET patients.

OUTLINE: This is a dose-escalation study of veliparib.

Patients receive capecitabine orally (PO) twice daily (BID) on days 1-14, temozolomide PO BID on days 10-14 and veliparib PO BID on days 10-14. Courses repeat every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor

A Phase 1 Study of Veliparib (ABT-888) in Combination With Capecitabine and Temozolomide in Advanced Well-Differentiated Neuroendocrine Tumors

National Cancer Institute (NCI)

Vanderbilt-Ingram Cancer Center

Professor of Medicine

Antibodies

Nivolumab

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive nivolumab IV over 30 minutes every 2 weeks in the absence of disease progression or unacceptable toxicity.

Benedito Carneiro, MD

The primary objective will be to assess overall response rate of nivolumab in patients with metastatic or locally advanced adrenocortical carcinoma. Nivolumab was recently approved by U.S. Food and Drug Administration (FDA) for the treatment of advanced melanoma, non-small cell lung cancer and renal cell carcinoma. It is considered investigational for the treatment of advanced or refractory adrenocortical carcinoma. "Investigational" means that the drug is not approved by the USFDA or not approved for the indication under investigation. Nivolumab could shrink adrenocortical carcinoma but it could also cause side effects. Researchers hope to learn if the study drug will shrink the cancer and hopefully to relieve symptoms that are related to the cancer.

PRIMARY OBJECTIVES:

I. To assess overall response rate of nivolumab in patients with metastatic or locally advanced adrenocortical carcinoma (ACC).

SECONDARY OBJECTIVES:

I. To assess the progression free survival defined as time from date of first nivolumab infusion until date of death or evidence of progression of disease as assessed by computed tomography (CT) imaging every 8 weeks according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1.

II. To assess the overall survival defined as time from date of first nivolumab infusion until death of patients with metastatic or locally advanced ACC.

III. To assess the safety and tolerability profile of nivolumab described by number, frequency, and severity of adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.3 assessed every 2 weeks while patients are on therapy.

TERTIARY OBJECTIVES:

I. To assess the overall response rate, progression free survival and overall survival according to tumor programmed cell death 1 ligand 1 (PD-L1) and programmed cell death 1 ligand 2 (PD-L2) expression.

II. To assess the overall response rate, progression free survival and overall survival according to serum interleukin levels and peripheral T cell profile levels.

III. To measure humoral and cellular responses to tumor antigens on serum samples by measuring the levels of cytokines (ie, interleukin \[IL\] -2, IL-6, IL-8, IL-10, IL-18, interferon \[IFN\] gamma and tumor necrosis factor \[TNF\]-alpha) and peripheral blood lymphocyte phenotype.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30 minutes every 2 weeks in the absence of disease progression or unacceptable toxicity, or withdrawal of consent.

After completion of study treatment, patients are followed up every 3 months for up to 2 years.

Nivolumab in Treating Patients With Metastatic Adrenocortical Cancer

Phase II Study of Nivolumab (Anti-PD-1 Antibody) for Treatment of Metastatic Adrenocortical Carcinoma

Humoral and cellular responses to tumor antigens on serum samples will be evaluated by measuring the levels of cytokines (ie, IL-2, IL-6, IL-8, IL-10, IL-18, IFN gamma and TNF-alpha). Potential correlations between differential measures of response and the toxicity and efficacy of nivolumab will be explored.

Humoral and cellular responses to tumor antigens on serum samples will be evaluated by measuring the levels of peripheral blood lymphocyte phenotype. Potential correlations between differential measures of response and the toxicity and efficacy of nivolumab will be explored.

PD-L1 expression will assist in assessing Overall response rate, PFS, and OS for this treatment.

PD-L2 expression will assist in assessing Overall response rate, PFS, and OS for this treatment.

Peripheral T cell profile levels will assist in assessing Overall response rate, PFS, and OS for this treatment.

Serum interleukin levels will assist in assessing Overall response rate, PFS, and OS for this treatment.

Overall Response Rate of nivolumab treatment for patients with metastatic adrenocortical carcinoma will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI scans every 8 weeks:

Complete Response (CR) = disappearance of all target lesions. Partial Response (PR) \>=30% decrease in the sum of the longest diameter of target lesions (should be confirmed 8 weeks after initial response otherwise considered unconfirmed PR).

Stable Disease, neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study.

Progressive Disease, defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions..

Progression Free Survival (PFS) of nivolumab treatment in patients with metastatic adrenocortical carcinoma is defined as the duration of time from start of treatment to time of documented progression or death, whichever comes first. It will measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI scans every 8 weeks.

Overall Survival (OS) of nivolumab treatment in patients with metastatic adrenocortical carcinoma and will be defined as the duration of time from treatment initiation until death. OS will be assessed as the percentage of patients alive at 3 months and at 6 months from initiation of treatment on study.

Safety and tolerability profile of Nivolumab will be assessed by describing by number, frequency, and severity of Adverse Events (AEs) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.3. All AEs that were considered related to Nivolumab were collected and are shown below. Patients with multiple events in the same category are counted only once in that category. Patients with events in more than one category are counted in each of those categories. Categories with no events are not shown.

In general AEs will be graded according to the following:

Grade 1 = Mild AE Grade 2= Moderate AE Grade 3 = Severe AE Grade 4 = Life-threatening or disabling AE Grade 5 = Death related to AE

Northwestern University

Patients receive nivolumab IV over 30 minutes every 2 weeks in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Treatment (Nivolumab)

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

The study did not meet its first stage requirements of Interim analysis.

Devalingam Mahalingam

Complete Response

Unconfirmed Partial Response

Stable Disease

Progressive Disease

All patients that received one dose of nivolumab were evaluable for this objective.

Overall Response Rate

Progression-free Survival (PFS)

3 months

6 months

Overall Survival (OS) at 3 Months and 6 Months

Rash Grade 1-2

Nausea Grade 1-2

Cough Grade 1-2

Fatigue Grade 1-2

ALT Increase Grade 1-2

ALT Increase Grade 4

AST Increase Grade 1-2

AST Increase Grade 3

Bilirubin Elevation Grade 1-2

Hypokalemia Grade 3

Dehydration Grade 3

Mucositis Grade 1-2

Tremor Grade 3

Edema Grade 1-2

Immune Pneumonitis Grade 3

Immune Hepatitis Grade 3

Toxicity of Nivolumab

Levels of Cytokines

Levels of Peripheral Blood Lymphocyte Phenotype

PD-L1 Expression

PD-L2 Expression

Peripheral T Cell Profile Levels

Serum Interleukin Levels

3 Months

6 Months

Progression Free Survival (PFS) of nivolumab treatment in patients with metastatic adrenocortical carcinoma is defined as the duration of time from start of treatment to time of documented progression or death, whichever comes first. It will measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI scans every 8 weeks. PRS rate at 3 months and 6 months will be calculated as the percentage of patients that have not yet progressed at that timepoint.

Progression Free Survival Rate at 3 Months and 6 Months

Treatment on Study

Follow Up for 2 Years

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor	NCT02831179	Functional Panc... Malignant Somat... Merkel Cell Car... Metastatic Adre... Metastatic Carc... Multiple Endocr... Multiple Endocr... Multiple Endocr... Neuroendocrine ... Non-Functional ... Pancreatic Gluc... Pancreatic Insu... Recurrent Adren... Recurrent Adren... Recurrent Merke... Somatostatin-Pr... Stage III Adren... Stage III Thyro... Stage IIIA Merk... Stage IIIB Merk... Stage IV Adrena... Stage IV Merkel... Stage IVA Thyro... Stage IVB Thyro... Stage IVC Thyro... Thymic Carcinoi... VIP-Producing N... Well Differenti... Zollinger Ellis...	Capecitabine Temozolomide Veliparib Pharmacological... Laboratory Biom...	18 Years -	Vanderbilt-Ingram Cancer Center
Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor	NCT02831179	Functional Panc... Malignant Somat... Merkel Cell Car... Metastatic Adre... Metastatic Carc... Multiple Endocr... Multiple Endocr... Multiple Endocr... Neuroendocrine ... Non-Functional ... Pancreatic Gluc... Pancreatic Insu... Recurrent Adren... Recurrent Adren... Recurrent Merke... Somatostatin-Pr... Stage III Adren... Stage III Thyro... Stage IIIA Merk... Stage IIIB Merk... Stage IV Adrena... Stage IV Merkel... Stage IVA Thyro... Stage IVB Thyro... Stage IVC Thyro... Thymic Carcinoi... VIP-Producing N... Well Differenti... Zollinger Ellis...	Capecitabine Temozolomide Veliparib Pharmacological... Laboratory Biom...	18 Years -	Vanderbilt-Ingram Cancer Center
Nivolumab in Treating Patients With Metastatic Adrenocortical Cancer	NCT02720484	Metastatic Carc... Recurrent Adren... Stage III Adren... Stage IV Adrena...	Laboratory Biom... Nivolumab	18 Years -	Northwestern University

Spots Global Cancer Trial Database for recurrent adrenal cortex carcinoma