Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma

Browse trials for

• Melanoma 3,006
• Melanoma, Cutaneous Malignant 134

Keywords

• Melanoma
• Cutaneous melanoma
• Skin disease
• Skin cancer
• Skin Neoplasms
• Neoplasm Metastasis

Melanoma

3,006 studies on the registry are indexed under Melanoma; 520 are open to participants now.

This study's enrollment of 402 is above the median of 38 across 2,351 interventional studies indexed under Melanoma.

Lead sponsor

Pfizer is the lead sponsor of 3,244 studies on the registry; 139 are open to participants now.

Of its 582 completed or terminated interventional studies of FDA-regulated products, 381 (65%) have results posted.

Study arms

• Experimental
  MEK162

  Drug: MEK162

• Active comparator
  Dacarbazine

  Drug: Dacarbazine

Interventions

• DrugMEK162

  MEK162 will be administered as a fixed dose of 45 mg (3 x 15 mg tablets) BID, with a glass of water and taken with or without food.

• DrugDacarbazine

  Patients randomized to dacarbazine will receive an IV infusion of dacarbazine 1000 mg/m2 over the course of 1 hour on day 1 and then every three weeks.

Primary outcomes

1. Progression-Free Survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

   PFS: time from randomization to first documented PD or death due to any cause, whichever occurred first. RECIST 1.1, PD: \>=20% increase in sum of diameter of target lesions (TLs) taking as reference the smallest sum on study (including baseline sum), sum must also be an absolute increase of \>=5 mm; unequivocal progression of existing non-TLs; appearance of \>=1 lesion. Complete response (CR): disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to \<10 mm; normalization of tumor marker level for non-TLs. Partial response (PR): \>=30% decrease in sum of diameter of all TLs, referring baseline sum of diameters. Stable disease (SD): neither sufficient shrinkage to qualify for PR nor increase in lesions qualified for PD referring smallest sum diameter. With no event at time of analysis cut-off or at start of any new anti-neoplastic therapy, PFS censored at date of last adequate tumor assessment of CR, PR or SD.

   Time frame: From the date of randomization to the date of the first documented PD or death, whichever occurred first (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)

Secondary outcomes

1. Overall Survival (OS)

   Overall survival was defined as the time from the date of randomization to the date of death due to any cause. If a participant was not known to have died, overall survival was censored at the date of last known date participant alive.

   Time frame: From the date of randomization to the date of death (maximum up to 107 weeks for binimetinib arm; maximum up to 88 weeks for dacarbazine arm)

2. Overall Response Rate (ORR)

   ORR: percentage of participants with best overall response (BOR) of CR or PR. BOR: best response recorded from start of treatment until CR or PR. RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to \<10 mm; normalization of tumor marker level for non-TLs; b) PR: \>=30% decrease in sum of diameter of all TLs, taking as reference baseline sum of diameters. ORR is reported for confirmed and unconfirmed responses. Confirmed CR or PR = at least 2 determinations of CR or PR at least 4 weeks apart before PD. PD: \>=20% increase in sum of diameter of all measured target lesions, taking as reference smallest sum of diameter of all TLs recorded at or after baseline, sum must also be absolute increase of \>=5 mm. Unequivocal progression of existing non TLs. Appearance of at least 1 new lesion.

   Time frame: From date of randomization until first documented response of CR or PR (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)

3. Time to Response (TTR)

   TTR: time between date of randomization until first documented response of CR or PR. RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to \<10 mm; normalization of tumor marker level for non-TLs; b) PR: \>=30% decrease in sum of diameter (dia) of all TLs, referring baseline sum of dia; c) PD: \>=20% increase in sum of diameter of all measured TLs taking as reference smallest sum of diameter of all TLs recorded at or after baseline, sum must also be absolute increase of \>=5 mm. Unequivocal progression of existing non-TLs. Appearance of \>=1 new lesion. Participants who did not achieve PR or CR censored at last adequate tumor assessment date when they did not have PFS event (time from date of randomization to date of first documented PD or death due to any cause, whichever occur first) or at maximum follow-up when they had PFS event.

   Time frame: From date of randomization until first documented response of CR or PR (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)

4. Duration of Objective Response (DOR)

   DOR: time from date of first documented response (CR or PR) to first documented progression or death due to underlying cancer. RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to \<10 mm; normalization of tumor marker level for non-TLs; b) PR: \>=30% decrease in sum of diameter (dia) of all TLs, referring baseline sum of dia; c) PD: \>=20% increase in sum of diameter of all measured target lesions taking as reference smallest sum of diameter of all target lesions recorded at or after baseline, sum must also be absolute increase of \>=5 mm. Unequivocal progression of existing non-target lesions. Appearance of at least 1 new lesion. If a participant with a CR or PR had no PD or death due to underlying cancer, participants was censored at date of last adequate tumor assessment.

   Time frame: From the date of first documented response (CR or PR) to the first documented progression or death (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)

5. Disease Control Rate (DCR)

   DCR was calculated as the percentage of participants with a BOR of CR, PR, SD RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to \<10 mm; normalization of tumor marker level for non-TLs; b) PR: \>=30% decrease in sum of diameter of all target lesions, taking as reference the baseline sum of diameters; c) SD: neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD taking as reference the smallest sum diameters; d) PD: \>=20% increase in sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline, sum must also be absolute increase of \>=5 mm. Unequivocal progression of existing non-target lesions. Appearance of at least 1 new lesion.

   Time frame: From date of randomization until first documented response of CR, PR, SD or non-CR/non-PD (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)

6. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

   An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. SAE was defined as one of the following: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. Treatment-emergent AE was defined as an AE with onset date occurring during the on-treatment period. AEs included all SAEs and non-SAEs.

   Time frame: From baseline up to 219.4 weeks for binimetinib arm; From baseline up to 123.9 weeks for dacarbazine arm

7. Number of Participants With Clinically Notable Hematology Shifts Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.03

   Clinically notable shifts are defined as worsening by at least 2 grades or to \>= grade 3. Severity was graded as Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.

   Time frame: From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

8. Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03

   Clinically notable shifts are defined as worsening by at least 2 grades or to \>= grade 3. Severity was graded as Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.

   Time frame: From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

9. Number of Participants With Clinically Notable Vital Signs

   Abnormalities criteria included: low/high pulse rate (beats per minute \[bpm\]):\<=50bpm with decrease from baseline \>=15bpm/\>=120bpm with increase from baseline \>=15bpm; Low/high systolic blood pressure (millimeters of mercury \[mmHg\]): \<=90mmHg with decrease from baseline \>=20mmHg/\>=160mmHg with increase from baseline \>=20mmHg; Low/high diastolic blood pressure \[mmHg\]: \<=50mmHg with decrease from baseline \>=15mmHg/\>=100mmHg with increase from baseline \>=15mmHg; Low/high body weight (kilogram \[kg\]): \>=20% decrease from baseline / \>=10% increase from baseline; Low/high body temperature (degree Celsius \[°C\]): \<=36°C / \>= 37.5°C

   Time frame: From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

10. Number of Participants With Notable Electrocardiogram (ECG) Values

    Criteria for notable ECG values were as follow: QT interval (in millisecond \[msec\]) new (newly occurring post-baseline value) greater than (\>) 450, 480, 500, increase from baseline \>30, increase from baseline \>60; corrected QT interval by Fredericia formula (QTcF) in msec new (newly occurring post-baseline value) \> 450, 480, 500, increase from baseline \>30, increase from baseline \>60; corrected QT interval by Bazett's formula (QTcB) in msec new (newly occurring post-baseline value) \> 450, 480, 500, increase from baseline \>30, increase from baseline \>60; heart rate in bpm new (newly occurring post-baseline value) \<60 and \>100.

    Time frame: From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

11. Number of Participants With Adverse Events of Special Interest: Cardiac Events

    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. Here, in this outcome measure data is reported for events falling in any of the grades.

    Time frame: From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

12. Number of Participants With Clinically Significant Findings in Physical Examination

    A complete physical examination included the examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and neurological systems. If indicated based on medical history and/or symptoms, rectal, external genitalia, breast, and pelvic examinations were performed. Clinical significance in physical examination was reported as adverse events.

    Time frame: From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

13. Number of Participants With Adverse Events of Special Interest: Ocular Events

    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. Grade 1: Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental ADL; Grade 3: Severe or medically significant but not immediately sight threatening; Hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-care ADL; Grade 4: Sight-threatening consequences; urgent intervention indicated; blindness (20/200 or worse) in the affected eye. Here, in this outcome measure data is reported for events falling in any of the grades.

    Time frame: From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

14. Plasma Concentration of Binimetinib

    Time frame: Day 1 of Week 1: Pre-dose, 1, 1.5, 2, 10 hours post-dose; Day 1 of Weeks 4, 7: Pre-dose, 1.5 hours post-dose; Day 1 of Weeks 10, 13: Pre-dose

15. Time to Definitive 10% Deterioration in Global Health Status Score of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30)

    The time to definitive 10% deterioration was defined as the time from the date of randomization to the date of event, which was defined as death due to any cause or at least 10% worsening of the corresponding scale score, relative to baseline, with no later improvement above this threshold observed during the course of the study or death due to any cause. If a participant had no event prior to analysis cut-off or start of another anticancer therapy, time to deterioration was censored at the date of the last adequate health related quality of life (HRQoL) evaluation. EORTC QLQ-C30: 5 functional scales (physical, role, cognitive, emotional, and social), a global health status scale, 3 symptom scales (nausea/vomiting, pain, fatigue) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). All scales and single-item measures range =0 to 100. High score for global health status = high quality of life.

    Time frame: From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

16. Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6

    EORTC QLQ-C30: 5 functional scales (physical, role, cognitive, emotional, and social), a h global health status scale, 3 symptom scales (nausea/vomiting, pain, fatigue) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). All scales and single-item measures range =0 to 100. High score for global health status = high quality of life. Post-treatment tumor assessments follow up visits occurred at every 9 weeks if participants started new anticancer therapy.

    Time frame: Both arms: Baseline, Day 1 Treatment Week (TW) 4,7,13,19,25,34,43,52; Post-treatment follow-up Visit (FUV) 1 to 6; Binimetinib: Day 1 TW61,70; End of treatment (EOT= TW73); Safety FUV=30 days post TW73; Dacarbazine: EOT=TW 57;Safety FUV=30 days post TW57

17. Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6

    EQ-5D-5L, is a standardized measure of health utility that provides a single index value for one's health status. EQ-5D-5L contained 1 item for each of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension has 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, and 5= extreme problems. Index score: participant responses to the 5 dimensions reflected a specific health state that corresponded to a population preference weight for that state on a continuous scale of 0 (death) to 1 (perfect health). Higher index scores = better health state. Post-treatment tumor assessments follow up visits occurred at every 9 weeks if participants started new anticancer therapy.

    Time frame: Both arms: Baseline, Day 1 Treatment Week (TW) 4,7,13,19,25,34,43,52; Post-treatment follow-up Visit (FUV) 1 to 6; Binimetinib: Day 1 TW61,70; End of treatment (EOT= TW73); Safety FUV=30 days post TW73; Dacarbazine: EOT=TW 57;Safety FUV=30 days post TW57

18. Time to Definitive 1 Point Deterioration in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)

    ECOG PS was used to assess the physical health of participants, and ranged from 0 (most active) to 5 (dead). ECOG PS grades: 0= fully active, able to carry on all pre-disease performance without restriction, 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work, 2= ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours, 3= capable of only limited self-care, confined to bed or chair more than 50% of waking hours, 4=completely disabled. cannot carry on any selfcare. Totally confined to bed or chair and 5= dead. Definitive deterioration is defined as on treatment death due to any cause or decrease in ECOG PS by at least one category from baseline score.

    Time frame: From baseline up to 73 weeks 3 days for binimetinib arm; From baseline up to 57 weeks 3 days for dacarbazine arm

19. Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)

    ECOG PS was used to assess the physical health of participants, and ranged from 0 (most active) to 5 (dead). ECOG PS grades: 0= fully active, able to carry on all pre-disease performance without restriction, 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work, 2= ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours, 3= capable of only limited self-care, 4=completely disabled. cannot carry on any selfcare. Totally confined to bed or chair confined to bed or chair more than 50% of waking hours and 5= dead. Post-treatment tumor assessments follow up visits occurred at every 9 weeks if participants started new anticancer therapy.

    Time frame: For both arms: Baseline, Weeks 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55 and 30-day Follow-up For binimetinib only: Weeks 58, 61, 64, 67, 70, 73

20. Number of Participants With Neuroblastoma RAS Viral (V-ras) Oncogene Homolog (NRAS) Mutation Status at Baseline

    Number of participants with NRAS mutation status at baseline were reported.

    Time frame: Baseline

Baseline characteristics

Publications

• Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, Di Giacomo AM, Rutkowski P, Del Vecchio M, Gutzmer R, Mandala M, Thomas L, Demidov L, Garbe C, Hogg D, Liszkay G, Queirolo P, Wasserman E, Ford J, Weill M, Sirulnik LA, Jehl V, Bozon V, Long GV, Flaherty K. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Apr;18(4):435-445. doi: 10.1016/S1470-2045(17)30180-8. Epub 2017 Mar 9. PubMed 28284557 ↗

Individual participant data

Plan to share: Yes — Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.