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Report for Clinical Trial NCT01989585

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Phase I/II Study of Dabrafenib, Trametinib, and Navitoclax in BRAF Mutant Melanoma (Phase I and II) and Other Solid Tumors (Phase I Only)

This phase I/II trial studies the side effects and best dose of dabrafenib, trametinib, and navitoclax and to see how well they work in treating patients with BRAF mutant melanoma or solid tumors that have spread to other parts of the body (metastatic) or cannot be removed by surgery (unresectable). Dabrafenib, trametinib, and navitoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT01989585 Metastatic Melanoma Solid Neoplasm Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Unresectable Melanoma
MeSH:Melanoma Skin Neoplasms
HPO:Cutaneous melanoma Melanoma Neoplasm of the skin

5 Interventions

Name: Dabrafenib

Description: Given PO
Type: Drug
Group Labels: 2

Arm I (dabrafenib, trametinib) Arm II (dabrafenib, trametinib, and navitoclax)

Name: Laboratory Biomarker Analysis

Description: Correlative studies
Type: Other
Group Labels: 2

Arm I (dabrafenib, trametinib) Arm II (dabrafenib, trametinib, and navitoclax)

Name: Navitoclax

Description: Given PO
Type: Biological
Group Labels: 1

Arm II (dabrafenib, trametinib, and navitoclax)

Name: Pharmacological Study

Description: Correlative studies
Type: Other
Group Labels: 2

Arm I (dabrafenib, trametinib) Arm II (dabrafenib, trametinib, and navitoclax)

Name: Trametinib

Description: Given PO
Type: Drug
Group Labels: 2

Arm I (dabrafenib, trametinib) Arm II (dabrafenib, trametinib, and navitoclax)


Primary Outcomes

Description: Determined by dose-limiting toxicities graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events.

Measure: Recommended phase II dose of the combination of dabrafenib, trametinib, and navitoclax (Phase I)

Time: Up to 28 days

Description: Assessed per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, in the cohort of patients treated with dabrafenib, trametinib, and navitoclax (DTN). The proportion of patients with a best response of CR will be presented with a 95% confidence interval calculated using the method of Atkinson and Brown.

Measure: Proportion of patients with a complete response (CR) (Phase II)

Time: Up to 4 weeks after last study treatment

Description: A comparison between the maximal tumor regression for patients treated with DTN and dabrafenib and trametinib (DT) will be conducted using a Wilcoxon rank-sum test.

Measure: Maximal degree of tumor regression (Phase II)

Time: Up to 4 weeks after last study treatment

Secondary Outcomes

Description: PFS will be summarized using the Kaplan-Meier. Log-rank tests will be used to assess for indications of differences between the two treatment modalities.

Measure: Progression free survival (PFS) (Phase II)

Time: Time from start of treatment to time of progression or death, whichever occurs first, assessed for up to 4 years

Description: OS will be summarized using the Kaplan-Meier. Log-rank tests will be used to assess for indications of differences between the two treatment modalities.

Measure: Overall survival (OS) (Phase II)

Time: Up to 4 years

Description: ORRs will be presented with 95% exact, binomial confidence intervals.

Measure: Objective response rate (ORR) (Phase II)

Time: Up to 4 weeks after last study treatment

Other Outcomes

Description: Fold changes of TUNEL will be calculated (post/pre). A Wilcoxon rank-sum test will be used to compare the ratios (or equivalently, the difference in the natural logs) of baseline and follow-up levels of TUNEL between DTN and DT treatment arms.

Measure: Change in terminal deoxynucleotidyl transferase 2´-deoxyuridine, 5´-triphosphate (dUTP) nick end labeling assay (TUNEL) staining

Time: Baseline to up to 1 week

Description: Will be primarily descriptive.

Measure: Change in B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL-2)

Time: Baseline to up to 1 week

Description: Will be primarily descriptive.

Measure: Change in Ki67

Time: Baseline to up to 1 week

Description: Will be primarily descriptive.

Measure: Change in phosphatase and tensin homolog (PTEN) status

Time: Baseline to up to 1 week

Description: Fold-changes in assay response will be calculated (post/pre). Fold changes in the assay will be compared across RECIST responses using the Kruskal-Wallis test. In addition, for assay-based response or progression, the proportions of patients with CR/partial response (PR), stable disease (SD), or progressive disease (PD) will be presented with exact 90% confidence intervals. Assay performance data will be compared with response. The proportions will be summarized and compared using exact confidence intervals. Behavior of the blood assay will be summarized graphically.

Measure: Fold changes in BRAF-mutation assay

Time: Baseline to up to 4 weeks after last study treatment

Description: Assay fold changes will be compared with fold changes in tumor burden (post/pre). The relationship will be summarized graphically and using the Spearman rank correlation. Differences in the behavior of the assay will be explored using a general linear model of log (fold-change) with study, baseline tumor burden, and log (fold-change tumor burden) as predictors.

Measure: Fold changes in tumor burden

Time: Baseline to up to 4 weeks after last study treatment

Description: 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.

Measure: Pharmacokinetic parameters, including maximal plasma or serum concentration (Cmax), area under the curve to the last collection point (AUClast), area under the curve for dose interval (AUC0-t), and time of maximal concentration (Tmax)

Time: Pre-treatment, 1, 2, 4, 6, 8, and 24 hours post-treatment on days 1 and 15 of cycle 1, and day 1 of cycles 2, 4, 8, and 12

Purpose: Treatment

Allocation: Randomized

Parallel Assignment


There is one SNP

SNPs


1 V600E

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.. Inclusion Criteria: - PHASE I SUBJECTS ONLY: Prior therapy is allowed; for patients enrolled in the Phase I portion of the study, patients may have received any number of prior lines of therapy including treatment with a BRAF and/or MEK inhibitor; prior navitoclax use will not be allowed, unless the patient received < 7 days of navitoclax lead-in on this or another study and had to stop for reasons other than toxicity or disease progression - Patients must have histologically confirmed, BRAF-mutant (V600E/K) melanoma (molecularly confirmed using validated, commercially available assay performed in a Clinical Laboratory Improvement Act [CLIA]-approved laboratory) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective - If test at CLIA-certified lab used a non-Food and Drug Administration (FDA) approved method, information about the assay must be provided; (FDA approved tests for BRAF V600 mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test) - Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Prior therapy is allowed; for patients enrolled in the Phase II portion of the study, patients may have received prior immunotherapy (including high-dose IL-2, ipilimumab, nivolumab, and other anti-PD1/PDL1 antibodies) or chemotherapy; however prior navitoclax, BRAF inhibitor and/or MEK inhibitor therapy will not be allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1 x 10^9/L - Hemoglobin >= 9 g/dl (patients may be transfused to this level) - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x institutional upper limit of normal OR > 1.5 x institutional upper limit of normal allowed if direct bilirubin is within normal range - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.3 x upper limit of normal (ULN) - Serum creatinine =< 1.5 mg/dL OR creatinine clearance >= 50 mL/min/1.73 --- V600E ---

thyroiditis/hypothyroidism, adrenal insufficiency, hypophysitis) requiring replacement therapy, at the time of randomization - Due to the expected dose-limiting toxicity of thrombocytopenia, the following concomitant medications are not allowed during navitoclax administration: clopidogrel, ibuprofen, tirofiban, warfarin, and other anticoagulants, drugs, or herbal supplements that affect platelet function are excluded, with the exception of low-dose anticoagulation medications (such as heparin) that are used to maintain the patency of a central intravenous catheter; aspirin will not be allowed within 7 days prior to the first dose of navitoclax or during navitoclax administration; however, subjects who have previously received aspirin therapy for thrombosis prevention may resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable (>= 50,000/mm^3) through 6 weeks of navitoclax administration; all decisions regarding treatment with aspirin therapy will be determined by the investigator in conjunction with the medical monitor - Current use of a prohibited medication; the following medications or non-drug therapies are prohibited: - Other anti-cancer therapy while on study treatment; (note: megestrol [Megace] if used as an appetite stimulant is allowed) - Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis - Because the composition, pharmacokinetics (PK), and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - Anticoagulants or antiplatelet agents except for low-dose, aspirin - Preclinical studies indicate that navitoclax is metabolized by CYP3A4, is a moderate inhibitor of CYP2C8, and is a strong inhibitor of CYP2C9; there is also evidence of interactions with dabrafenib; therefore, caution should be exercised when dosing navitoclax concurrently with CYP2C8 and CYP2C9 substrates; common CYP2C8 substrates include paclitaxel, statins, and glitazones, whereas CYP2C9 substrates include phenytoin; when possible, investigators should switch to alternative medications or monitor the patients closely; CYP3A inhibitors such as ketoconazole and clarithromycin are not allowed 7 days prior to the first dose of navitoclax or during navitoclax administration - Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A or CYP2C8 are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of permeability-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded; below are a few examples of the agents: - Strong inducers of CYP3A or CYP2C8: - Antibiotics: rifamycin class agents (e.g., rifampin, rifabutin, rifapentine) - Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin, s-mephenytoin - Miscellaneous: bosentan, St. John's wort - Strong inhibitors of CYP3A or CYP2C8 - Antibiotics: clarithromycin, telithromycin, troleandomycin - Antidepressants: nefazodone - Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole - Hyperlipidemia: gemfibrozil - Antiretroviral: ritonavir, saquinavir, atazanavir - Miscellaneous: conivaptan Inclusion Criteria: - PHASE I SUBJECTS ONLY: Prior therapy is allowed; for patients enrolled in the Phase I portion of the study, patients may have received any number of prior lines of therapy including treatment with a BRAF and/or MEK inhibitor; prior navitoclax use will not be allowed, unless the patient received < 7 days of navitoclax lead-in on this or another study and had to stop for reasons other than toxicity or disease progression - Patients must have histologically confirmed, BRAF-mutant (V600E/K) melanoma (molecularly confirmed using validated, commercially available assay performed in a Clinical Laboratory Improvement Act [CLIA]-approved laboratory) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective - If test at CLIA-certified lab used a non-Food and Drug Administration (FDA) approved method, information about the assay must be provided; (FDA approved tests for BRAF V600 mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test) - Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Prior therapy is allowed; for patients enrolled in the Phase II portion of the study, patients may have received prior immunotherapy (including high-dose IL-2, ipilimumab, nivolumab, and other anti-PD1/PDL1 antibodies) or chemotherapy; however prior navitoclax, BRAF inhibitor and/or MEK inhibitor therapy will not be allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1 x 10^9/L - Hemoglobin >= 9 g/dl (patients may be transfused to this level) - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x institutional upper limit of normal OR > 1.5 x institutional upper limit of normal allowed if direct bilirubin is within normal range - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.3 x upper limit of normal (ULN) - Serum creatinine =< 1.5 mg/dL OR creatinine clearance >= 50 mL/min/1.73 --- V600E ---



HPO Nodes


HPO:
HP:0008069: Neoplasm of the skin
Genes 277
TGFBR2 DOCK8 KRT17 PORCN ERCC4 OCA2 PTEN SDHC SUFU RNF6 KRT6B PIK3CA TNFRSF1B DDB2 KRT14 SDHD FASLG COL1A1 CARMIL2 LRRC8A BAP1 NF1 FLT4 NRAS LAMC2 RSPO1 OCRL TP53 NTHL1 PTEN NF1 FH LAMB3 COL7A1 PERP FH NRAS TINF2 SLC17A9 RECQL4 PTCH2 RPS20 CD79B KRT17 BMPR1A MLH1 NF1 GJB3 LZTS1 MSH3 SUFU GNA14 IKBKG PTCH1 KIT HRAS BRAF APC PRKAR1A MMP1 KRT17 TP53 KEAP1 SMO PTCH1 ERCC5 MVD TERC PTEN SEMA4A CD79A SMARCB1 GJB2 KIT FLT4 KRT9 MC1R SEC23B VEGFC ERCC3 FGFR1 BLNK TNFRSF1B MSH6 TCF3 PLCD1 MEN1 FAS KRAS CTSC RECQL4 CD28 CDKN2B WWOX CTLA4 COL7A1 HRAS CDKN2A TP53 WNT10A NLRP1 ERCC2 IFNG MBTPS2 MDM2 KRAS GTF2E2 MLH1 STAT1 TMC8 SNAI2 BMPR1A CDKN1A KDSR CD28 CYLD ERCC2 ERCC4 NRAS DCLRE1C SLC45A2 PMS1 MITF MSH3 NUTM1 IL7 PIK3CA ERCC3 SDHC PTCH2 MLH1 CIB1 MSH6 CDKN2A NF1 CIB1 TNFRSF10B NF2 APC SLCO2A1 BLM GJA1 GTF2H5 PIK3CA TARS1 CXCR4 CDK4 PIK3R1 CYLD GJC2 GPR143 DDB2 LAMA3 SDHB MVK PMVK PIK3CA EPCAM GJB2 NF2 MSH2 WRAP53 MEN1 RASA1 KRAS LMNA CTNNB1 CDKN1B POLH GJB6 MPLKIP IL6 CXCR4 NOTCH3 TSC2 AKT1 PSENEN PMS2 RASGRP1 CASP10 ERCC3 MC1R SDHB KIT RMRP PTEN TGFBR2 PDGFRB CYLD RNF113A ALX3 BLM CTNNB1 FH KIT STIM1 TYR TMC6 HRAS CHEK2 KRT1 DICER1 DKC1 MSH2 COL7A1 NRAS PTEN FDPS PRKCD NRAS CDKN2A XPC WNT10A SEC23B XPA CDKN1B ERCC2 HPGD ERCC5 SLX4 TNFRSF4 FCN3 MMP1 ECM1 USF3 LMNA XPC NTHL1 KRT16 KIT PDGFB FAN1 ERCC4 SPRED1 PDGFB ING1 FERMT1 MLH1 KLLN ERCC2 GJB4 MSH6 APC TERT POLH BRD4 WRN SASH1 TMC6 MSH2 HRAS APC PMS2 ERCC3 KIT CTLA4 KLLN IGHM STK4 FAS GJB2 MLH3 TRPV3 CDKN2C IGLL1 TYR MSH2 NF2 COL7A1 AKT1 DCC FLCN PTCH1 TSC1 CDKN2A KRT5 PRKAR1A
Protein Mutations 4
D299G P13K V600E V600K
SNP 0