Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Melanoma, Cutaneous Malignant

Skin Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Trametinib

Dabrafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Onalespib

Pharmacological Study

Ryan J Sullivan

This phase I trial studies the side effects and best dose of onalespib when given together with dabrafenib and trametinib in treating patients with BRAF-mutant melanoma or solid tumors that have spread to another place in the body (metastatic) or cannot be removed by surgery. Onalespib, dabrafenib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD), toxicity, and safety profile of onalespib (AT13387) given weekly in combination with dabrafenib and trametinib in patients with BRAF-mutant metastatic or unresectable solid tumors.

SECONDARY OBJECTIVES:

I. To obtain preliminary estimates of the objective response rate (ORR) and progression-free survival (PFS) and document the 6-month PFS and 1-year overall survival (OS) of patients with BRAF-mutant metastatic or unresectable melanoma treated with AT13387 given weekly in combination with dabrafenib and trametinib.

II. To describe the pharmacokinetics of treatment with dabrafenib, trametinib, and AT13387.

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

Patients receive dabrafenib orally (PO) twice daily (BID), trametinib PO once daily (QD) on days 1-28, and onalespib intravenously (IV) over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days and every 6 months for up to 2 years.

Onalespib, Dabrafenib, and Trametinib in Treating Patients With BRAF-Mutant Melanoma or Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

Phase I Study of AT13387 in Combination With Dabrafenib and Trametinib in Patients With BRAF-Mutant Melanoma and Other Solid Tumors

Descriptive statistics including mean, standard deviation, coefficient of variation, geometric mean, median, minimum and maximum will be computed for each pharmacokinetic variable; descriptive statistics for natural-log transformed pharmacokinetic variables will also be provided.

Will be performed to assess how changes in the expression of the key signaling proteins relate to patient response.

Toxicities will be graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 5.0. Toxicity rates will be summarized with a 90% exact binomial confidence interval.

The response rate will be presented as a point estimate with a 90% exact binomial confidence interval.

The distribution of progression-free survival will be summarized using the product-limit method of Kaplan-Meier.

Median times for each endpoint will be presented with two-sided, 90% confidence intervals estimated using log(-log\[survival\]) methodology. Kaplan-Meier estimates of 6-month progression-free survival will also be presented with two-sided, 90% confidence intervals.

The distribution of overall survival will be summarized using the product-limit method of Kaplan-Meier. Kaplan-Meier estimates of 1-year overall survival will also be presented with two-sided, 90% confidence intervals.

The one-year disease-free survival after treatment will be estimated using the product-limit methods of Kaplan-Meier, and presented with 90% confidence intervals.

National Cancer Institute (NCI)

Gland and Hormone Related Diseases

Carcinoma

Thyroid Neoplasms

Thyroid Diseases

Thyroid Carcinoma, Anaplastic

Endocrine System Diseases

Endocrine Gland Neoplasms

Head and Neck Neoplasms

Neoplasms, Glandular and Epithelial

Anaplastic Thyroid Cancer

Intensity-Modulated Radiation Therapy

Sasan Fazeli, MD

Sasan M. Fazeli, MD

Manisha H. Shah, MD

Naifa Busaudy, MD

This trial studies how well dabrafenib, trametinib, and intensity modulated radiation therapy (IMRT) work together in treating patients with BRAF mutated anaplastic thyroid cancer. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy beams to kill tumor cells and shrink tumors. Giving dabrafenib, trametinib, and IMRT together may kill more tumor cells.

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability (maximum tolerated dose \[MTD\]) of concurrent intensity modulated radiation therapy (IMRT) and BRAF-MEK inhibitors dabrafenib and trametinib in patients with BRAF-mutated anaplastic thyroid cancer.

SECONDARY OBJECTIVES:

I. To assess overall objective response rate, time to progression of local recurrence, progression free survival and overall survival.

II. To assess pharmacokinetics during concurrent IMRT and dabrafenib plus trametinib therapy.

III. To assess pharmacodynamics of dabrafenib plus trametinib induction therapy.

IV. To assess mechanism of resistance to dabrafenib plus trametinib and radiation therapy.

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

INDUCTION: Patients receive dabrafenib orally (PO) twice daily (BID) and trametinib PO once daily (QD) for 7-28 days in the absence of disease progression and unacceptable toxicity.

OPTIONAL SURGERY: Patients with resectable disease may undergo surgery 3 days after stop treatment of dabrafenib/trametinib, and move to Concurrent Radiation 14 days after surgery provided that surgical wound has healed. All other patients continue to receive dabrafenib PO BID and trametinib PO QD in the absence of disease progression and unacceptable toxicity.

CONCURRENT RADIATION: Patients receive dabrafenib PO BID and trametinib PO QD at weeks 6-7. Within 2.5 hours of morning doses of dabrafenib/trametinib administration, patients undergo intensity modulated radiation therapy (IMRT) on Monday-Friday delivered over 6.5 weeks in the absence of disease progression or unacceptable toxicity.

POST-RADIATION: Patients receive dabrafenib PO BID and trametinib PO QD for 4 weeks in the absence of disease progression and unacceptable toxicity.

MAINTENANCE: Patients with residual disease receive dabrafenib PO BID and trametinib PO QD in the absence of disease progression and unacceptable toxicity. Patients stop dabrafenib and trametinib 8 weeks after achieving complete response. Patients with no residual disease stop dabrafenib and trametinib, with the option of restarting dabrafenib and trametinib at time of disease recurrence.

After completion of study treatment, patients are followed up every 2 months for 1 year.

Dabrafenib, Trametinib, and IMRT in Treating Patients With BRAF Mutated Anaplastic Thyroid Cancer

A Phase I Trial of Concurrent Intensity Modulated Radiation Therapy (IMRT) and Dabrafenib/Trametinib in BRAF Mutated Anaplastic Thyroid Cancer

Will be defined as the proportion of patients who have a partial response (PR), or complete response (CR) within the first 4 weeks of IMRT. Complete response (CR) and partial response (PR) will be defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will be calculated with the exact binomial 95% confidence intervals.

Will be evaluated by RECIST criteria for disease limited to the radiation field (neck) following the first set of scans after completion of IMRT. Estimated by Kaplan-Meier method.

City of Hope Medical Center

Nivolumab

Antibodies

Antibodies, Monoclonal

Ipilimumab

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive dabrafenib PO BID and trametinib PO QD for 25 days. Patients then receive ipilimumab IV over 90 minutes. Treatment with ipilimumab repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients receive dabrafenib PO BID and trametinib PO QD for 25 days followed by nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 4 doses, followed by nivolumab monotherapy IV every 2 weeks continuously for up to 42 courses.

Patients receive trametinib PO QD for 25 days. Patients then receive ipilimumab IV over 90 minutes. Treatment with ipilimumab repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients receive trametinib PO QD for 25 days followed by nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 4 doses, followed by nivolumab monotherapy IV every 2 weeks continuously for up to 42 courses.

Patients receive dabrafenib PO BID for 25 days. Patients then receive ipilimumab IV over 90 minutes. Treatment with ipilimumab repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients receive dabrafenib PO BID for 25 days followed by nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 4 doses, followed by nivolumab monotherapy IV every 2 weeks continuously for up to 42 courses.

Patients receive ipilimumab IV over 90 minutes Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 4 doses, followed by nivolumab monotherapy IV every 2 weeks continuously for up to 42 courses

Patrick A Ott

This randomized phase I trial studies the side effects and best way to give ipilimumab with or without dabrafenib, trametinib and/or nivolumab in treating patients with melanoma that has spread to other parts of the body (metastatic) or cannot be removed by surgery. Monoclonal antibodies, such as ipilimumab and nivolumab, may interfere with the ability of cancer cells to grow and spread. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether ipilimumab works better with or without dabrafenib, trametinib, and/or nivolumab in treating melanoma.

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of ipilimumab (part 1) or ipilimumab plus nivolumab (part 2) following lead-in of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors, either alone or in combination, in patients with BRAFV600 mutant melanoma.

SECONDARY OBJECTIVES:

I. To determine the response rate to ipilimumab (part 1) or ipilimumab plus nivolumab (part 2) after BRAF and MEK inhibitors, either alone or in combination, compared to no prior kinase inhibitor treatment.

II. To determine the safety and tolerability of dabrafenib and trametinib combination in the setting of prior ipilimumab alone or ipilimumab preceded by BRAF and MEK inhibitors, either alone or in combination (part 1).

III. To determine the safety and tolerability of dabrafenib and trametinib combination in the setting of prior ipilimumab plus nivolumab without prior BRAF/MEK inhibition or ipilimumab plus nivolumab preceded by BRAF and MEK inhibitors, either alone or in combination (part 2).

IV. To determine the response rate to dabrafenib and trametinib in the setting of prior ipilimumab alone or ipilimumab preceded by BRAF and MEK inhibitors, either alone or in combination (part 1).

V. To determine the response rate to dabrafenib and trametinib in the setting of prior ipilimumab plus nivolumab without prior MEK/BRAF inhibition or prior ipilimumab plus nivolumab preceded by BRAF/MEK inhibitors (part 2).

VI. To obtain peripheral blood and tumor tissue for biomarker analysis. VII. To describe the immune impact of kinase inhibitor therapy on the immune response associated with ipilimumab treatment (part 1) or ipilimumab plus nivolumab treatment (part 2).

VIII. To observe and record anti-tumor activity.

OUTLINE: Patients are randomized to 1 of 4 treatment arms for Part 2 (Part 1 closed to accrual 8/25/2015).

PART 1: (Closed to accrual as of 8/25/2015) ARM A1: Patients receive dabrafenib orally (PO) twice daily (BID) and trametinib PO once daily (QD) for 25 days. Patients then receive ipilimumab intravenously (IV) over 90 minutes. Treatment with ipilimumab repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

ARM B1: Patients receive trametinib PO QD for 25 days. Patients then receive ipilimumab IV over 90 minutes. Treatment with ipilimumab repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

ARM C1: Patients receive dabrafenib PO BID for 25 days. Patients then receive ipilimumab IV over 90 minutes. Treatment with ipilimumab repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

ARM D1: Patients receive ipilimumab IV over 90 minutes. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

PART 2:

ARM A2: Patients receive dabrafenib PO BID and trametinib PO QD for 25 days followed by nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 4 doses, followed by nivolumab monotherapy IV every 2 weeks continuously for up to 42 courses.

ARM B2: Patients receive trametinib PO QD for 25 days followed by nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 4 doses, followed by nivolumab monotherapy IV every 2 weeks continuously for up to 42 courses.

ARM C2: Patients receive dabrafenib PO BID for 25 days followed by nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 4 doses, followed by nivolumab monotherapy IV every 2 weeks continuously for up to 42 courses.

ARM D2: Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 4 doses, followed by nivolumab monotherapy IV every 2 weeks continuously for up to 42 courses.

After 12 weeks of treatment with ipilimumab, or ipilimumab and nivolumab followed by nivolumab monotherapy, all patients may continue to receive dabrafenib PO BID and trametinib PO QD in the absence of disease progression.

After completion of study treatment, patients are followed up for 14 weeks.

Ipilimumab With or Without Dabrafenib, Trametinib, and/or Nivolumab in Treating Patients With Melanoma That Is Metastatic or Cannot Be Removed by Surgery

A Sequential Safety and Biomarker Study of BRAF-MEK Inhibition on the Immune Response in the Context of Combined CTLA-4 Blockade and PD-1 Blockade for BRAF Mutant Melanoma

The relationship between pre-treatment marker levels and response will be assessed according to expression cut-off between positive and negative. Fisher's exact test will be used to detect an increase in response rate and a secondary, sensitivity analysis will use a stratified Fisher's exact test.

Biomarkers measured on a continuous scale will be summarized and compared across response categories using the Wilcoxon rank-sum test. For biomarkers measured categorically, pre/post response combinations will be compared between responders and non-responders using Fisher's exact test.

Presented with 90% confidence intervals calculated using exact binomial methods.

Presented with 90% confidence intervals calculated using exact binomial methods by randomized treatment arm.

Summarized by treatment arm and presented with 90% exact binomial confidence intervals. Fisher's exact test will be used.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Onalespib, Dabrafenib, and Trametinib in Treating Patients With BRAF-Mutant Melanoma or Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery	NCT02097225	BRAF V600E Muta... BRAF V600K Muta... Metastatic Mali... Metastatic Mela... Stage III Cutan... Stage IIIA Cuta... Stage IIIB Cuta... Stage IIIC Cuta... Stage IV Cutane... Unresectable So...	Dabrafenib Laboratory Biom... Onalespib Pharmacological... Trametinib	18 Years -	National Cancer Institute (NCI)
Dabrafenib, Trametinib, and IMRT in Treating Patients With BRAF Mutated Anaplastic Thyroid Cancer	NCT03975231	BRAF NP_004324.... BRAF V600K Muta... Thyroid Gland A...	Dabrafenib Intensity-Modul... Trametinib	18 Years -	City of Hope Medical Center
Ipilimumab With or Without Dabrafenib, Trametinib, and/or Nivolumab in Treating Patients With Melanoma That Is Metastatic or Cannot Be Removed by Surgery	NCT01940809	BRAF V600E Muta... BRAF V600K Muta... Metastatic Mela... Stage III Cutan... Stage IIIA Cuta... Stage IIIB Cuta... Stage IIIC Cuta... Stage IV Cutane...	Dabrafenib Ipilimumab Laboratory Biom... Nivolumab Trametinib	18 Years -	National Cancer Institute (NCI)
Onalespib, Dabrafenib, and Trametinib in Treating Patients With BRAF-Mutant Melanoma or Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery	NCT02097225	BRAF V600E Muta... BRAF V600K Muta... Metastatic Mali... Metastatic Mela... Stage III Cutan... Stage IIIA Cuta... Stage IIIB Cuta... Stage IIIC Cuta... Stage IV Cutane... Unresectable So...	Dabrafenib Laboratory Biom... Onalespib Pharmacological... Trametinib	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for braf v600k mutation present