Symptoms and General Pathology

All Conditions

Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Recurrence

Carcinoma

Small Cell Lung Carcinoma

Carcinoma, Neuroendocrine

Lung Neoplasms

Neuroendocrine Tumors

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Disease Attributes

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Adenocarcinoma

Small Cell Lung Cancer

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Temozolomide

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Patients receive nivolumab IV on day 1 of a 28 day cycle. Patients also receive temozolomide PO on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Dwight Owen, MD, MS

This phase II trial studies how well nivolumab and temozolomide work in treating patients with small-cell lung cancer that has come back or does not respond to treatment, or neuroendocrine cancer that has spread to other places in the body. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. 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 nivolumab and temozolomide may work better in treating patients with small-cell lung cancer and neuroendocrine cancer.

PRIMARY OBJECTIVES:

I. To evaluate the efficacy (using response rate per RECIST v1.1) of nivolumab and temozolomide for the treatment of patients with either small cell lung cancer that have progressed or recurred after prior platinum-based chemotherapy and immunotherapy (cohort 1), or progressive metastatic neuroendocrine carcinoma of any grade or primary site in any line of therapy (cohort 2).

SECONDARY OBJECTIVES:

I. To evaluate the safety profile and toxicity of combination nivolumab and temozolomide as per Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 5.0.

II. To evaluate the progression free survival (PFS) and overall survival (OS) of patients treated with combination nivolumab and temozolomide.

III. To evaluate the central nervous system (CNS) PFS of patients with small cell lung cancer (SCLC) treated with nivolumab and temozolomide.

EXPLORATORY OBJECTIVES:

I. To determine whether treatment with nivolumab and temozolomide leads to a decrease in immune-suppressive cell populations (ie myeloid-derived suppressor cells \[MDSC\]) in peripheral blood.

II. To determine whether objective response rate (ORR), PFS, OS vary by tumor O6-methylguanine deoxyribonucleic acid (DNA) methyltransferase (MGMT) methylation at baseline.

III. To determine whether baseline tumor mutational burden is predictive of response to therapy in patients with SCLC treated with nivolumab and temozolomide.

IV. To determine whether changes in blood based mutation burden during treatment may predict clinical benefit.

V. To determine whether a composite immune and tumor cell staining score can be developed with or without PD-L1 by immunohistochemistry (IHC) to predict response in the SCLC cohort.

OUTLINE:

Patients receive nivolumab intravenously (IV) on day 1 of a 28 day cycle. Patients also receive temozolomide orally (PO) on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 8 weeks for 12 months, then every 12 weeks thereafter.

Nivolumab and Temozolomide in Treating Patients With Recurrent or Refractory Small-Cell Lung Cancer or Advanced Neuroendocrine Cancer

A Phase II, Multi-Cohort Trial of Combination Nivolumab and Temozolomide in Recurrent/Refractory Small-Cell Lung Cancer and Advanced Neuroendocrine Tumors

The study will evaluate PD-L1 by immunohistochemistry (IHC), and assess the clinical outcomes (ie OS) between patients with high expression and low expression of PD-L1.

Response will be defined by a complete response (CR) or partial response (PR), confirmed or unconfirmed. Response will be defined for patients with measurable disease and who receive at least one dose of combination treatment. Exact binomial 95% confidence intervals for the true PR+CR response rate will be calculated.

Attribution to drug, time-of-onset, duration of the event, resolution, and any concomitant medications administered will be recorded. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either ?unrelated? or ?unlikely to be related? to study treatment in the event of an actual relationship developing.

CNS PFS will be measured for patients with relapsed vs refractory small-cell lung cancer (SCLC) in cohort 1. The Kaplan-Meier method will be used.

Bristol-Myers Squibb

Dwight Owen

Principal Investigator

Carcinoma, Small Cell

Antibodies

Antibodies, Monoclonal

Ipilimumab

Immunoglobulins

Patients receive cabozantinib s-malate PO QD on days 1-21 of cycles 1-4 and days 1-28 of subsequent cycles, nivolumab IV over 30 minutes on day 1, and ipilimumab IV over 90 minutes on day 1 of cycles 1-4 only. Treatment repeats every 21 for 4 cycles then every 28 days for subsequent cycles in the absence of disease progression or unacceptable toxicity.

Cabozantinib S-malate

Anteneh A Tesfaye

This phase II trial studies how well the combination of XL184 (cabozantinib), nivolumab, and ipilimumab work in treating patients with poorly differentiated neuroendocrine tumors (i.e., neuroendocrine tumor that does not look like the normal tissue it arose from). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving cabozantinib, nivolumab and ipilimumab may shrink the cancer.

PRIMARY OBJECTIVE:

I. To evaluate the overall response rate (ORR) associated with the combination of XL184 (cabozantinib), nivolumab, and ipilimumab in patients with advanced poorly-differentiated neuroendocrine carcinomas (NECs), after the failure of at least one line of prior therapy.

SECONDARY OBJECTIVES:

I. To evaluate progression-free survival (PFS). II. To measure the safety and tolerability of the combination of XL184 (cabozantinib), nivolumab, and ipilimumab in patients with advanced, poorly-differentiated NECs.

III. To evaluate disease control rate (DCR). IV. To measure duration of response (DOR). V. To describe the tumor molecular profile using whole exome sequencing (WES) and correlate it with treatment outcome.

VI. To describe the tumor molecular profile using ribonucleic acid (RNA) sequencing (RNAseq) and correlate it with treatment outcome.

EXPLORATORY OBJECTIVES:

I. To measure the tumor-infiltrating CD8+ T lymphocytes in pre- and on-treatment biopsies.

II. To measure tumor-infiltrating myeloid derived suppressor cells (MDSCs) in pre- and on-treatment biopsies.

III. To measure tumor-infiltrating tumor-associated macrophages (TAM) in the pre and on-treatment biopsies.

IV. To measure the expression of programmed death-ligand 1 (PD-L1) in tumor cells and infiltrating immune cells.

OUTLINE:

Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-21 of cycles 1-4 and days 1-28 of subsequent cycles, nivolumab intravenously (IV) over 30 minutes on day 1, and ipilimumab IV over 90 minutes on day 1 of cycles 1-4 only. Treatment repeats every 21 for 4 cycles then every 28 days for subsequent cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks, and then every 3 months thereafter.

Testing the Combination of XL184 (Cabozantinib), Nivolumab, and Ipilimumab for Poorly Differentiated Neuroendocrine Tumors

A Phase 2 Study of XL184 (Cabozantinib) in Combination With Nivolumab and Ipilimumab for the Treatment of Poorly Differentiated Neuroendocrine Carcinomas

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.

Will be summarized with descriptive statistics (N, mean, standard deviation, median, interquartile range \[IQR\], minimum, maximum, and a CI for the mean). Statistical graphics (e.g., box plots, dot plots, etc.) will also be created to illustrate the distributions of the various correlative endpoints.

Will be summarized with descriptive statistics (N, mean, standard deviation, median, IQR, minimum, maximum, and a CI for the mean). Statistical graphics (e.g., box plots, dot plots, etc.) will also be created to illustrate the distributions of the various correlative endpoints.

Defined as complete responses (CR) plus partial responses (PR). Responses will be determined via Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. CR+PR rate will be summarized with a point estimate and a 2-sided Wilson type confidence interval (CI) estimate.

Analyzed with standard Kaplan-Meier methodology. Point and CI estimates of the median and various time point-specific rates will be derived from the Kaplan-Meier life table. Censored PFS will be analyzed for all registered patients.

Safety including specific toxicity types, grades, and attributions will be evaluated and summarized. Toxicity will be assessed in all toxicity-evaluable (t-e) patients using the Common Terminology Criteria for Adverse Events (CTCAE) 5.0 criteria. The t-e population is defined as all patients who have received the study treatment. The resulting binary endpoints of each toxicity type at a specific grade(s), will all be summarized with point estimates and 2-sided Wilson type CI estimates. The grade of each type of toxicity will also be summarized with 1-way frequency distributions.

The binary endpoint of DCR will be defined as the achievement of either CR, or PR, or stable disease (SD) (yes/no). The resulting binary endpoints of DCR will all be summarized with point estimates and 2-sided Wilson type CI estimates.

The censored time-to-event distributions of DOR will be analyzed with standard Kaplan-Meier methodology. Point and CI estimates of the median and various time point-specific rates will be derived from the Kaplan-Meier life table. Censored DOR will be analyzed for the combination of all patients who achieve either a CR or a PR.

National Cancer Institute (NCI)

Digestive System Diseases

Gland and Hormone Related Diseases

Pancreatic Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Irinotecan

Topotecan

Camptothecin

Topoisomerase I Inhibitors

Enzyme Inhibitors

Patients receive elimusertib PO BID on days 1 and 2 and irinotecan IV over 90 minutes on day 1 of each cycle. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT and/or MRI throughout the study, tumor biopsy at screening and on study, and collection of blood samples at screening.

Patients receive elimusertib PO QD on days 2, 3, 9, 10, 16, and 17 of cycle 1 and 2, and on days 2, 3, 9, and 10 of each cycle thereafter. Patients receive irinotecan IV over 90 minutes on days 1, 8, and 15 of cycle 1 and 2, and on days 1 and 8 of each cycle thereafter. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT and/or MRI throughout the study, tumor biopsy at screening and on study, and collection of blood samples at screening.

Patients receive elimusertib PO QD on days 2 and 5 and topotecan IV over 30 minutes on days 1-5 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT and/or MRI throughout the study, tumor biopsy at screening and on study, and collection of blood samples at screening.

Biopsy

Biospecimen Collection

Computed Tomography

Elimusertib

Irinotecan Hydrochloride

Magnetic Resonance Imaging

Topotecan Hydrochloride

Thatcher Heumann

This phase I trial investigates the side effects and best dose of BAY 1895344 when given together with usual chemotherapy (irinotecan or topotecan) in treating patients with solid tumors that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced), with a specific focus on small cell lung cancer, poorly differentiated neuroendocrine cancer, and pancreatic cancer. BAY 1895344 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as irinotecan and topotecan, 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. Adding BAY 1895344 to irinotecan or topotecan may help to slow the growth of tumors for longer than seen with those drugs alone.

PRIMARY OBJECTIVES:

I. To assess safety and tolerability of each of the elimusertib (BAY 1895344) plus topoisomerase 1 (top1) inhibitor (irinotecan hydrochloride \[irinotecan\] or topotecan hydrochloride \[topotecan\]) combinations.

II. To estimate maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of each of the combinations.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. To estimate objective response rate (ORR), progression free survival (PFS), overall survival (OS) and duration of response (DOR) in patients treated with each combination.

III. To estimate plasma pharmacokinetic (PK) characteristics of BAY 1895344 plus each top1 inhibitor (irinotecan or topotecan) when used in combination.

IV. To estimate changes in pharmacodynamic (PD) markers of deoxyribonucleic acid (DNA) damage (gamma-H2AX, phosphorylated \[p\]S343-NBS1) elicited by each combination from on-treatment tumor biopsies (in dose expansion cohorts only).

EXPLORATORY OBJECTIVES:

I. To estimate response outcomes (ORR, PFS, OS, DOR) in study patients by tumor ataxia telangiectasia mutated (ATM) expression loss (assessed by immunohistochemistry \[IHC\]).

II. To estimate response outcomes (ORR, PFS, OS, DOR) in study patients with tumor DNA damage response (DDR) mutations (assessed by whole exome sequencing \[WES\], ribonucleic acid \[RNA\] sequencing \[RNA Seq\], and circulating tumor DNA \[ctDNA\] analysis).

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 3 cohorts.

COHORT I: Patients receive elimusertib orally (PO) twice daily (BID) on days 1 and 2 and irinotecan intravenously (IV) over 90 minutes on day 1 of each cycle. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) throughout the study, tumor biopsy at screening and on study, and collection of blood samples at screening.

COHORT II: Patients receive elimusertib PO once daily (QD) on days 2, 3, 9, 10, 16, and 17 of cycle 1 and 2, and on days 2, 3, 9, and 10 of each cycle thereafter. Patients receive irinotecan IV over 90 minutes on days 1, 8, and 15 of cycle 1 and 2, and on days 1 and 8 of each cycle thereafter. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT and/or MRI throughout the study, tumor biopsy at screening and on study, and collection of blood samples at screening.

COHORT III: Patients receive elimusertib PO QD on days 2 and 5 and topotecan IV over 30 minutes on days 1-5 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT and/or MRI throughout the study, tumor biopsy at screening and on study, and collection of blood samples at screening.

After completion of study treatment, patients are followed every 2 months for up to 6 months.

Testing the Addition of an Anti-cancer Drug, BAY 1895344, to Usual Chemotherapy for Advanced Stage Solid Tumors, With a Specific Focus on Patients With Small Cell Lung Cancer, Poorly Differentiated Neuroendocrine Cancer, and Pancreatic Cancer

BAY 1895344 Plus Topoisomerase-1 (Top1) Inhibitors in Patients With Advanced Solid Tumors, Phase I Studies With Expansion Cohorts in Small Cell Lung Carcinoma (SCLC), Poorly Differentiated Neuroendocrine Carcinoma (PD-NEC) and Pancreatic Adenocarcinoma (PDA)

Will assess the prevalence of tumor ATM expression loss in all patients. Will also estimate response outcomes (ORR, PFS, OS, DOR) in study patients by tumor ATM expression loss.

Will assess the specific tumor DDR gene mutations present in study patients. Will also estimate response outcomes (ORR, PFS, OS, DOR) in study patients with tumors with DDR gene mutations.

Defined by occurrence of \>= 2 dose limiting toxicities (DLTs) defined as grade 4 neutropenia lasting \>= 7 days, grade 4 thrombocytopenia, grade 4 anemia, grade 3 neutropenia with fever, grade 3 thrombocytopenia with bleeding, any grade 3 hematologic toxicity lasting \>= 7 days (counting from first day of toxicity grade recognition) or any non-hematologic grade \>= 2 adverse events (AEs) lasting \>= 7 days (with the exception of grade 2 \[G2\] fatigue, G2 nausea or G2 diarrhea) (counting from first day of toxicity grade recognition) in any dose level during cycle 1 of treatment. DLTs will be graded by Common Terminology Criteria for Adverse Events version 5.0.

Grade 4 hematologic toxicity will be monitored using the Bayesian approach of Thall, Simon, Estey as extended by Thall and Sung. Clinical safety data (e.g. AEs) will be tabulated and summarized using descriptive statistics as requested by the sponsor investigator, executive committee, medical monitor or Data Safety Monitoring Board using methods described in the Data Safety Monitoring Plan.

Will be estimated by measuring the number of patients who achieve complete response or partial response by Response Evaluation Criteria in Solid Tumors 1.1 criteria on 12-week restaging computed tomography scans from the total number of patients who received the study treatment.

DOR will be estimated by the Kaplan-Meier method.

PFS will be estimated by the Kaplan-Meier method.

OS will be estimated by the Kaplan-Meier method.

Will be estimated for each study drug based upon plasma collections from cycle 1 in all study patients.

Will be estimated for expansion cohort only study patients.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Nivolumab and Temozolomide in Treating Patients With Recurrent or Refractory Small-Cell Lung Cancer or Advanced Neuroendocrine Cancer	NCT03728361	Grade I Neuroen... Grade II Neuroe... Grade III Neuro... Metastatic Neur... Neuroendocrine ... Recurrent Small... Refractory Smal... Lung Cancer Sta... Large Cell Neur... Neuroendocrine ... Small Cell Lung... Small-cell Lung...	Nivolumab Temozolomide	18 Years -	Ohio State University Comprehensive Cancer Center
Testing the Combination of XL184 (Cabozantinib), Nivolumab, and Ipilimumab for Poorly Differentiated Neuroendocrine Tumors	NCT04079712	Metastatic Larg... Metastatic Neur... Metastatic Neur... Metastatic Smal...	Cabozantinib S-... Ipilimumab Nivolumab	18 Years -	National Cancer Institute (NCI)
Testing the Addition of an Anti-cancer Drug, BAY 1895344, to Usual Chemotherapy for Advanced Stage Solid Tumors, With a Specific Focus on Patients With Small Cell Lung Cancer, Poorly Differentiated Neuroendocrine Cancer, and Pancreatic Cancer	NCT04514497	Metastatic Lung... Metastatic Mali... Metastatic Neur... Metastatic Panc... Stage III Lung ... Stage III Pancr... Stage IV Lung C... Stage IV Pancre... Unresectable Lu... Unresectable Ma... Unresectable Ne... Unresectable Pa...	Biopsy Biospecimen Col... Computed Tomogr... Elimusertib Irinotecan Hydr... Magnetic Resona... Topotecan Hydro...	18 Years -	National Cancer Institute (NCI)

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