Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor
Any number and type of prior anticancer therapies are allowed except BRAF or mitogen-activated protein kinase kinase (MEK) inhibitors
Patients with BRAF-positive tumor(s) are eligible for the study if they received prior treatment with a BRAF inhibitor (alone of in combination with a MEK inhibitor) or declined targeted therapy.
Progressing following PD-1 based checkpoint inhibitor therapy, with or without ipilimumab; tumors harboring BRAF V600 alterations must also have received prior therapy with BRAF inhibitors (with or without a MEK inhibitor) (for treatment phase)
Prior therapy with BRAF/MEK agents within 3 weeks prior to first day of study treatment (for treatment phase)
History of prior significant toxicity (Grade 2 or higher that required permanent treatment discontinuation) from a BRAF, MEK (MAPK [Mitogen-activated protein]/ERK kinase) or ERK inhibitor.
No prior therapy with inhibitors affecting the mitogen-activated protein kinase (MAPK) pathways at any level (BRAF, mitogen-activated protein [MAP]/extracellular signal-related kinase [ERK] kinase [MEK], neuroblastoma RAS viral [v-ras] oncogene homolog [NRAS], ERK inhibitors) for unresectable stage IIIC or stage IV (metastatic) melanoma; no limit to other therapies (immunotherapy or chemotherapy); prior systemic treatment in the adjuvant setting is allowed; (note: ipilimumab treatment must end at least 8 weeks prior to study day 1)
Prior therapy with compounds targeting PD-1, PD-L1, BRAF, mitogen-activated protein kinase (MEK) or other molecules in the mitogen-activated protein kinase (MAPK) pathway
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
For enrollment to the phase II portion: participants who have not received prior BRAF or MEK inhibitor therapy
For enrollment to the phase I portion: there is no required washout period for BRAF or MEK inhibitor therapy
For enrollment to the phase II portion: participants who have received prior BRAF or MEK inhibitor therapy
The melanoma must harbor an activating BRAF V600 mutation; prior therapy with a BRAF and/or MEK inhibitor is allowed in the dose-escalation phase only; however, patients who discontinued previous RAF inhibitor due to intolerance of the drug rather than due to progression will not be eligible
In the dose expansion phase of the trial, prior treatment with a BRAF inhibitor will be an exclusion criterion
Part B3: Have metastatic melanoma carrying BRAF mutation, refractory/relapsed after treatment with Raf and/or MEK inhibitors
Prior therapy with a BRAF and/or mitogen-activated protein kinase kinase (MEK) and/or extracellular signal-regulated kinase (ERK) inhibitors
Prior exposure to experimental treatment targeting rapidly accelerated fibrosarcoma (Raf), MAP kinase/ERK kinase (MEK), or the mitogen-activated protein kinase (MAPK) pathway
The patients BRAF mutation status at position 600 must be known prior to enrollment; patients with V600E mutations are eligible if they have failed an approved BRAF inhibitor or MEK inhibitor therapy or have been offered an approved BRAF inhibitor or MEK inhibitor therapy and refused
Treatment-naive and previously treated patients will be included; however, patients may not have received a BRAF or MEK inhibitor in the past 24 weeks
Subjects previously treated with BRAF/MEK inhibitor therapy in the past 24 weeks
For Combination Therapy cohort only: Prior therapy with MEK inhibitors.
Additional criteria for escalation cohorts: A) patients must have Ras pathway activation (RPA) (including KRAS, NRAS, NF1, HRAS, and BRAF); B) prior treatment with MEK inhibitors and/or PARP inhibitors is allowed
Prior treatment with a BRAF inhibitor
Treatment-naive and previously treated patients will be included; however, patients may not have received a BRAF, MEK or HSP90 inhibitor in the past
Subjects previously treated with BRAF, MEK or HSP90 inhibitor therapy
Prior treatment with vemurafenib or other BRAF inhibitor within 42 days of Study Day 1 of Period A
Prior systemic therapy is allowed, although appropriate washout is required for patients who have been on BRAF inhibitors (at least 7 days)
No prior treatment with agents targeting BRAF mutant tyrosine kinases or MEK inhibitors or radiation of target lesions
Prior BRAF or mitogen-activated protein kinase kinase (MEK) directed therapy; patients who have received prior interferon are eligible
Prior therapy is allowed; patients may have received any number of prior lines of therapy, including treatment with a BRAF and/or MEK inhibitor
Has had prior systemic cancer therapy within the past four weeks or v-raf murine sarcoma viral oncogene homolog B (B-RAF) or mitogen-activated protein kinase (MEK) inhibitors within 7 days at the time of the start of the lymphodepletion regimen (Turnstile II)
Prior exposure to mitogen-activated protein kinase kinase (MEK), RAS, or RAF inhibitors (note: previous exposure to sorafenib is allowed) OR history of hypersensitivity to selumetinib, thyrotropin alpha (Thyrogen), or any excipient agents
Has had prior B-RAF or mitogen-activated protein kinase kinase (MEK) targeted therapy within 7 days prior to the start of lymphodepletion regimen (Cohort A and Cohort B)
Histologically or cytologically confirmed BRAF- or MEK-mutated melanoma
Approved BRAF and MEK inhibitors ? 3 weeks
Methotrexate or non-BRAF/MEK non-cytotoxic anti-tumor drug ? 2 weeks
Must have progressed on at least one prior line of platinum-based therapy for stage IV NSCLC (excluding docetaxel or mitogen activated protein kinase kinase [MEK] inhibitors)
Melanoma patients must be intolerant of, or have disease that has proven refractory to approved therapies such as B-Raf proto-oncogene, serine/threonine kinase (BRAF) or mitogen-activated protein kinase kinase 1 (MEK1) inhibitors for BRAF-positive metastatic melanoma and/or checkpoint blockade with either anti-programmed cell death 1 (PD1) or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) for metastatic melanoma
Prior exposure to Bcl-2 inhibitors, murine double minute 2 (MDM2) antagonists or prior exposure to experimental treatment targeting Raf, mitogen-activated protein kinase (MEK), or the mitogen-activated protein kinase (MAPK) RAS/RAF/MEK/ERK MAPK pathway
Subjects who are unable to tolerate BRAF inhibitor and/or MEK inhibitor therapy due to grade >= 2 toxicity (Common Terminology Criteria for Adverse Events [CTCAE] version [v]4.0) from these agents, irrespective of antitumor response, are eligible on condition that: (a) toxicities persisted despite change from doublet to singlet therapy (i.e. from concurrent BRAF inhibition plus MEK inhibition to BRAF inhibition alone), (b) toxicities are attributed to a class effect, and therefore switch from one drug to another is expected to induce the same type of toxicity (e.g. ocular toxicities or cardiac dysfunction from MEK inhibitor), (c) drug-specific toxicities that do not resolve with switch from one BRAF inhibitor to another (i.e. dabrafenib to vemurafenib, or vice versa), will be eligible for enrollment in 9922; in other words, patients will be allowed to enroll into the NCI9922 study despite lack of progression to MAPK inhibitor treatments, on condition that grade 2 or higher toxicities attributed to MAPK inhibitors resolve to grade 1, or less, at the time of study enrollment
Prior chemotherapy, including targeted therapy such as v-raf murine sarcoma viral oncogene homolog B1 (BRAF) or mitogen-activated protein kinase kinase (MEK) inhibition
Study participants with a history of prior treatment with BRAF or MEK inhibitors
Patients who have had prior therapy with a MEK inhibitor or an inhibitor of mutant BRAF are ineligible; because sorafenib has low efficacy as a BRAF inhibitor, prior therapy with it is allowed
Previous BRAF inhibitor treatment
For advanced disease, interleukin-2 at any dose and/or IFN-? (any formulation, no washout required); MEK and BRAF inhibitors: washout for at least 4 weeks prior to the start of dosing in this study
BRAF/MEK inhibitors within 2 weeks prior to the first dose of study treatment.
Patients may not have received prior MEK, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), or v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor therapy
Receipt of prior mitogen-activated protein kinase inhibitor pathway agents including mitogen-activated protein kinase inhibitor and BRAF kinase inhibitor
If the patient has disease with a BRAF mutation, s/he must have received treatment with appropriate BRAF/MEK inhibitor as single agent therapy or in combination, or be intolerant to, or refuse such treatment.
Prior BRAF or MEK inhibitor treatment is not required. However, for patients with known BRAF status:
Prior BRAF or MEK inhibitor therapy
Patients progressing on a prior BRAF inhibitor-based therapy will be eligible, as are patients nave to BRAF inhibitor therapy; resistance to BRAF inhibitor-based therapy will be defined as progressive disease by RECIST 1.1 criteria while receiving therapy with a BRAF inhibitor (vemurafenib or dabrafenib, alone or in combination with a mitogen-activated protein kinase [MEK] inhibitor); this may be innate resistance (patients who never achieved a tumor response while on BRAF inhibitor therapy) or acquired resistance (progression after having a tumor response to BRAF inhibitor therapy); there will not be a period of break between progression on the prior BRAF inhibitor-based therapy and the start of dabrafenib, trametinib and GSK2141795
Patients must have received prior BRAF inhibitor therapy (e.g. dabrafenib, vemurafenib) within 56 days prior to registration; prior trametinib therapy is permitted; patients are not required to interrupt BRAF or MEK inhibitor therapy prior to the initiation of three agent combination therapy on study
Any number and type of prior anticancer therapies except BRAF or mitogen-activated protein kinase (MEK) inhibitors
Patients with prior exposure to BRAF or MEK inhibitors are not eligible
Prior therapy with a MEK or BRAF inhibitor.
For Part 2 of the Study only, patients must have measurable disease by RECIST 1.1 and be in one of the the groups below. Patients in groups 1, 2, 4, 5 and 6 may not have been previously treated with BRAF and/or MEK inhibitors
Group 3: Patients with BRAF mutated melanoma who have progressed on, or are refractory to BRAF and/or MEK inhibitors
Prior treatment with MEK or BRAF inhibitors
Prior therapy with ipilimumab, other BRAF inhibitors, or mitogen-activated protein kinase (MEK) inhibitors
Any prior use of a BRAF or MEK inhibitor
Dose Expansion phase: Previous treatment with RAF or MEK inhibitors
BRAF/MEK inhibitors within 2 weeks prior to first dose of study treatment.
Prior systemic treatments with either ipilimumab or a BRAF inhibitor (such as vemurafenib or dabrafenib)
Previous treatment with selective/specific BRAF or Methyl Ethyl Ketone (MEK) inhibitor (previous treatment with sorafenib is allowed)
SELUMETINIB ARM: Any prior exposure to mitogen-activated protein kinase kinase (MEK), rat sarcoma (Ras), or v-raf-1 murine leukemia viral oncogene homolog 1 (Raf) inhibitors
Prior treatment with any BRAF inhibitor or any mitogen-activated protein/extracellular signal-regulated kinase inhibitor.
Previous treatment with a BRAF or MEK inhibitor
Prior therapy (except for adjuvant immunotherapy) with a BRAF and/or mitogen-activated protein kinase kinase (MEK) and/or extracellular signal-regulated kinase (ERK) inhibitors
Not a candidate for targeted therapy with BRAF or combined BRAF/MEK inhibitors (e.g., failed or did not tolerate prior therapy, BRAF V600 wild-type or due to drug unavailability or standard of care)
Part B, Part C and Part D only: Previous treatment with dabrafenib or any BRAF inhibitor, trametinib or another MEK inhibitor, or and Extracellular signal-regulated kinase inhibitor (exception: prior treatment with sorafenib is permitted). Patients who have received prior dabrafenib or another BRAF inhibitor may enrol into Part B4. Patients who have had prior dabrafenib or BRAF inhibitor therapy may enroll in Part C or Part D if they have had prior benefit to dabrafenib or BRAF inhibitor monotherapy, as determined by the investigator.
No prior therapy with a BRAF inhibitor or mitogen-activated protein kinase kinase (MEK) inhibitor or leflunomide
Previous treatment with a BRAF or MEK inhibitor.
Part A and Part B: Prior exposure to BRAF or MEK inhibitors unless approved by the GSK Medical Monitor.
Part C: Prior exposure to BRAF or MEK inhibitors. Prior anti-cancer therapy in the metastatic setting, with the exception of up to one regimen of chemotherapy and/or interleukin-2 (IL-2).
Part D: Prior exposure to BRAF inhibitors. A washout period of 6 weeks is required for ipilimumab.
At least 28 days from prior treatment (including adjuvant interferon) except in the case of a v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor (such as vemurafenib); concurrent treatment with a BRAF inhibitor +/- mitogen activate protein kinase kinase (MEK) inhibitor is permitted; concurrent treatment with an anti-programmed death-1 (PD1) agent is permitted
Prior exposure to BRAF or MEK inhibitors
Prior therapy with a BRAF inhibitor
Prior treatment with a BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor for metastatic melanoma (treatment in the adjuvant setting is allowed)
Prior treatment with vemurafenib or other BRAF inhibitor within 42 days of first dose of study drug
Prior treatment with MEK or v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors
Additional Inclusion Requirements for TAK-580 + nivolumab a) BRAF V600 mutation-positive or NRAS mutation-positive disease previously untreated with RAF, MEK, or other inhibitors of the mitogen-activated protein kinase (MAPK) pathway. Participants who have progressed on these agents can still be enrolled in TAK-202 (plozalizumab) + nivolumab or vedolizumab + nivolumab + ipilimumab.
Prior treatment with a MEK inhibitor or ERK inhibitor
Prior systemic therapy with a MEK inhibitor
Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab, panitumumab or other EGFR inhibitors
Prior treatment with a MEK, Ras or Raf inhibitor
Prior navitoclax, BRAF inhibitor, and MEK inhibitor is prohibited; (exceptions for Phase I are described above)
Prior treatment with cobimetinib or a MEK inhibitor
Previous treatment with cobimetinib or any other mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor
Prior treatment with selumetinib or another specific MEK 1/2 inhibitor
If BRAFV600-mutant, refractory disease to at least one BRAF inhibitor and a MEK inhibitor (defined as progression while on treatment), or intolerance to these drugs
STRATUM B: Previous exposure to a MEK inhibitor (i.e., trametinib, selumetinib)
Prior therapy with a MEK inhibitor
Previous mitogen-activated protein kinase kinase (MEK) inhibitor use such as PD-0325901; CI1040; AS73026; GDC 0973; ARRY43182; GSK110212
Prior treatment with MEK inhibitor
Prior MEK inhibitor therapy is allowed
Prior treatment with a MAP-kinase pathway inhibitor (RAS, RAF, ERK, MEK)
Prior therapy with selumetinib or another specific mitogen-activated protein kinase kinase (MEK) inhibitor is not permitted
Previous MEK, retrovirus associated sequence (RAS), or RAF inhibitor use
Prior treatment with a BRAF inhibitor or a MEK inhibitor; treatment by localized radiotherapy is not an exclusion criterion if an interval of at least two weeks between the end of radiotherapy and initiation of protocol therapy is observed
Prior treatment with selumetinib or another specific MEK 1/2 inhibitor
Prior treatment with a mitogen-activated protein kinase kinase (MEK) inhibitor
Previous treatment with any MEK inhibitor
Any prior treatment with either a MEK, Ras, or Raf inhibitor for advanced or metastatic NSCLC.
Prior therapy with a MEK inhibitor
Part B: Prior treatment with a RAF or MEK pathway inhibitor, except BRAFmutant melanoma (Group 1)
Prior treatment with 1 BRAF inhibitor and/or 1 MEK inhibitor allowed
No history of prior exposure to a MEK inhibitor
Past treatment with any MEK or ERK inhibitor or with panitumumab
Prior MEK inhibitor or prior TAS-102 therapy
Previous MEK, RAS, or RAF inhibitor use
If BRAFV600-mutant, documented refractory disease to at least one BRAF inhibitor (dabrafenib or vemurafenib) and/or a MEK inhibitor (trametinib or cobimetinib), defined as progression of measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria while on treatment; subjects with MAPK inhibitor-intolerance are eligible if they meet criteria
Patients who have prior therapy with trametinib or any other MEK inhibitor
Subjects with B-Raf V600 (BRAFV600) mutated tumors who have received prior BRAF inhibitor therapy either alone or in combination with MEK inhibitor as their only prior systemic therapy are eligible.
Patients must not have been treated with any of the following prior to Step 1 Randomization:\r\n* Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR\r\n* BRAF inhibitor including, but not limited to, vemurafenib or dabrafenib; regorafenib is not considered a BRAF inhibitor for the purpose of determining trial eligibility\r\n* Mitogen-activated protein/extracellular signal–regulated kinase (MEK) inhibitor including, but not limited to, trametinib or selumetinib
Prior cytotoxic therapy and immunotherapy are allowed; for the dose escalation, prior targeted therapy with a MEK inhibitor, protein kinase C inhibitor, Akt, or mTOR inhibitor are allowed; for the dose expansion cohort, no prior MEK, protein kinase C (PKC), Akt, or mTOR inhibitors are allowed, and registration is limited to 10 total patients; local therapies such as radiofrequency ablation or cryotherapy for metastatic disease are permitted but must have been performed at least 21 days prior to initiation of study therapy; lesions treated with local or regional modalities such as radiofrequency ablation, or cryotherapy may not be used as target lesions unless they demonstrate growth over a minimum of 3 months on subsequent imaging studies
Prior treatment with a mitogen-activated protein kinase kinase (MEK) inhibitor of any kind
History of prior significant toxicity from another mitogen-activated protein kinase (MEK) pathway inhibitor requiring discontinuation of treatment
Prior treatment with a Mitogen-Activated protein Kinase (MEK) inhibitor or any docetaxel-containing regimen (prior treatment with paclitaxel is acceptable).
Prior therapy with a BRAF inhibitor and/or a MEK- inhibitor
Group 5: Patients with MEK mutated cancer
Prior therapy with a MEK- inhibitor
Prior treatment with a MEK (Mitogen-Activated Protein Kinase) inhibitor or any docetaxel-containing regimen (prior treatment with paclitaxel is acceptable)
Prior treatment with a selective inhibitor of RAF or MEK
Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib [GSK2118436], vemurafenib, and LX281/BMS-908662) or a MEK inhibitor (including but not limited to trametinib [GSK1120212], AZD6244, and RDEA119); NOTE: there is no limit to the number of other prior therapies, and patients may be previously untreated
Patients previously treated with potent BRAF inhibitor or MEK inhibitor, including PLX4032/vemurafenib, ARQ 736 for more than 10 days; previous treatment with sorafenib is permitted
Previous treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, LGX818, and XL281/BMS-908662) or MEK inhibitor (including but not limited to trametinib, AZD6244, and RDEA119) prior to start of study treatment (Note: Prior treatment with dabrafenib is allowed for crossover subjects in Cohort A);
Prior MEK inhibitor therapy is allowed
Patients who have received prior treatment with a MEK inhibitor
Prior therapy with a mitogen-activated protein kinase kinase (MEK)-inhibitor
Prior therapy with a MEK inhibitor
Patients who have had prior VEGF pathway inhibitor, BRAF or MEK inhibitor therapy are ineligible.
History of prior significant toxicity from another MEK inhibitor or ERK inhibitor requiring discontinuation of treatment
Prior therapy with a MEK- inhibitor
Prior treatment with a BRAF inhibitor or MEK inhibitor
History of prior significant toxicity from another MEK pathway inhibitor or combination of another MEK and epidermal growth factor receptor (EGFR) inhibitor requiring discontinuation of treatment
Previous treatment with a combination of a MEK inhibitor with an EGFR inhibitor (applies only to the indication specific expansion cohorts in Stage 2)
The subject has been previously treated with a Mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor.
Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, and XL281/BMS-908662) or a MEK inhibitor (including but not limited to trametinib, AZD6244, and RDEA119) or ipilimumab or any other agent targeting a T-cell immunomodulatory pathway (including, but not limited to CTLA-4, PD-1, 4-1BB, OX40, GITR, CD27, and CD28)
Prior therapy with a MEK inhibitor.
Part 2 ONLY: Previous treatment with dabrafenib, another RAF inhibitor, or a mitogen-activated protein kinase (MEK) inhibitor (exception: prior treatment with sorafenib is permitted).
Prior treatment with selumetinib or another specific mitogen-activated protein kinase (MEK)1/2 inhibitor (unless the subject meets criteria for re-treatment)
Subjects who have not yet initiated but plan to undergo dosing with a tyrosine kinase inhibitor (TKI) or Raf inhibitor, either alone or with a MEK inhibitor, for treatment of metastatic melanoma, colon cancer, hepatic cell carcinoma, or thyroid cancer
History of prior significant toxicity from another MEK or ERK inhibitor requiring discontinuation of treatment
Previous treatment with dabrafenib, trametinib, other RAF inhibitor, other MEK or ERK inhibitor