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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

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

Name: Laboratory Biomarker Analysis

Description: Correlative studies

Type: Other

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

Name: Navitoclax

Description: Given PO

Type: Biological

Arm II (dabrafenib, trametinib, and navitoclax)

Name: Pharmacological Study

Description: Correlative studies

Type: Other

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

Name: Trametinib

Description: Given PO

Type: Drug

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:
Cutaneous melanoma
Genes 15
HRAS MITF CDKN2A BRAF NRAS NRAS WRN CDKN2A CXCR4 BAP1 POLH CDK4 ERCC3 XPC MC1R
Melanoma
Genes 98
MGMT NRAS POT1 NRAS XPA CTSC BRCA1 SDHC ERCC4 CXCR4 RAD51C CDKN2B ERCC3 XPC PALLD ERCC2 ERCC2 CHEK2 CDKN2A RAD51D GNAQ SDHD KRAS MBTPS2 BAP1 BAP1 CYSLTR2 RNF43 BAP1 CDKN2A PTPN11 CDK4 BRCA2 ERCC3 MITF TERF2IP ERCC4 CHEK2 BRCA1 TRPV3 POT1 OCA2 TERT CDKN2A AKT1 CDKN2A SF3B1 ERCC6 ERCC5 ERCC5 MDM2 BRCA2 BAP1 GNA11 ACD BRIP1 HRAS MRE11 BRAF TYR TP53 KLLN SEC23B PTEN PIK3CA XPA PERP MITF RAF1 BRAF POLH TP53 BARD1 NRAS SMAD4 RAD50 DDB2 ERCC2 NBN TERT MC1R SLC45A2 WRN PALB2 DDB2 PALB2 CDKN2A SDHB MC1R RAD51 TP53 XPC ERCC3 PTEN CDKN2A POLH CDK4 MC1R
Neoplasm of the skin
Genes 274
COL7A1 LZTS1 GTF2H5 SDHC NRAS KRAS ERCC2 KIT CTSC RASA1 RECQL4 SUFU ERCC2 TGFBR2 PORCN ERCC4 TARS1 ERCC3 XPC ERCC2 FH KRT17 NTHL1 PTEN MSH3 PIK3CA RASGRP1 IL7 ERCC4 TNFRSF1B SDHD PRKCD CYLD MBTPS2 CXCR4 KIT BMPR1A FAN1 NF1 KRT1 MSH3 CDKN2B KEAP1 DICER1 TNFRSF4 PTCH2 TERC CDKN2A KDSR CIB1 GJB4 PTCH2 CDKN2C RNF113A DCC COL7A1 ERCC3 ERCC4 SNAI2 CHEK2 IFNG TMC6 COL1A1 TRPV3 GJC2 TINF2 FLT4 PRKAR1A MSH2 MLH1 STAT1 KRT6B HPGD CASP10 TERT NLRP1 ERCC5 NUTM1 SLCO2A1 RSPO1 MDM2 PTEN FCN3 KRT16 DOCK8 HRAS BRAF NF2 TYR KRT17 NF1 PSENEN WRAP53 RNF6 MEN1 TSC1 MSH2 CYLD PTEN PERP IGHM TP53 PDGFB KRAS POLH BMPR1A BLM NOTCH3 TNFRSF1B KRT5 MLH3 SUFU KRT9 CTLA4 FLCN CD28 DDB2 NRAS ECM1 CTNNB1 MSH2 COL7A1 FLT4 TCF3 MEN1 FH KRT17 SMO NRAS MMP1 LMNA FGFR1 MVK PTCH1 GPR143 APC NF1 PMS1 CDK4 APC NF2 WNT10A GJB6 TSC2 KIT BLNK SPRED1 AKT1 NRAS SDHC NTHL1 SMARCB1 GJB2 MLH1 PMS2 LMNA MSH6 CXCR4 LAMB3 CD79B MPLKIP NF2 CDKN2A KIT MSH6 PIK3CA BAP1 PDGFRB VEGFC KLLN RMRP HRAS CTLA4 LRRC8A FAS KRAS BRD4 CARMIL2 SDHB MSH2 WNT10A PRKAR1A CYLD KRT14 IGLL1 PIK3CA HRAS TYR ERCC3 MITF GJB3 CD79A GNA14 MLH1 CDKN1A RPS20 GJB2 SLX4 PTCH1 OCA2 TP53 APC CDKN2A CIB1 AKT1 CDKN2A FDPS STK4 ERCC5 LAMA3 TMC8 PDGFB ING1 MSH6 KIT GJA1 LAMC2 PIK3R1 CDKN1B OCRL BLM FH NF1 GTF2E2 EPCAM KLLN SEC23B TGFBR2 SEMA4A PIK3CA XPA SLC17A9 TNFRSF10B FAS DKC1 APC RECQL4 CD28 NRAS PTEN MLH1 DDB2 TMC6 CTNNB1 ERCC2 SASH1 MC1R PMS2 SLC45A2 MVD SEC23B KIT WRN PTEN ALX3 SDHB FERMT1 FASLG PMVK MMP1 HRAS COL7A1 TP53 XPC ERCC3 WWOX CDKN1B PLCD1 GJB2 PTCH1 IKBKG POLH MC1R DCLRE1C