Table 1 Melanoma trials evaluating combination checkpoint inhibition with anti-CTLA-4 plus anti- PD-1/PD-L1 monoclonal antibodies

Unresectable Stage III/stage IV malignant melanoma

Phase 1

Assess the safety of specified doses of NIVO + IPI combination therapy for up to 5.5 years; secondary outcome: assessment of tumor response

Cohort 1: induction with NIVO 0.3 mg/kg (Q3W for 21 weeks) + IPI 3 mg/kg (Q3W for 9 weeks), maintenance with NIVO 0.3 mg/kg + IPI 3 mg/kg (Q12W for a total of 84 weeks); cohort 2: induction with NIVO 1 mg/kg (Q3W for 21 weeks) + IPI 3 mg/kg (Q3W for 9 weeks), maintenance with NIVO 1 mg/kg + IPI 3 mg/kg (Q12W for 84 weeks); cohort 3: induction with NIVO 3 mg/kg (Q3W for 21 weeks) + IPI 3 mg/kg (Q3W for 9 weeks), maintenance with NIVO 3 mg/kg + IPI 3 mg/kg (Q12W for 84 weeks); cohort 4: induction with NIVO 10 mg/kg (Q3W for 21 weeks) + IPI 3 mg/kg (Q3W for 9 weeks), maintenance with NIVO 10 mg/kg + IPI 3 mg/kg (Q12W for a total of 84 weeks); cohort 5: induction with NIVO 10 mg/kg (Q3W for 21 weeks) + IPI 10 mg/kg (Q3W for 9 weeks), maintenance with NIVO 10 mg/kg + IPI 10 mg/kg (Q12W for 84 weeks); cohort 6: NIVO 1 mg/kg (Q2W for 96 weeks); cohort 7: NIVO 3 mg/kg (Q2W for 96 weeks); cohort 8: 4 doses of IPI 3 mg/kg + NIVO 1 mg/kg (Q3W for 12 weeks), then monotherapy with NIVO 3 mg/kg (Q2W for 96 weeks)

Completed, results available

53% patients had grade 3–4 AE; NIVO 0.3 mg/kg + IPI 3 mg/kg (n = 14): 1 year OS rate = 56%, median OS = 14.8 months; NIVO 1 mg/kg + IPI 3 mg/kg (n = 17): 1 year OS rate = 94%, median OS non recordable; NIVO 3 mg/kg + IPI 1 mg/kg (n = 16): 1 year OS rate = 89%, median OS non recordable; NIVO 3 mg/kg + IPI 3 mg/kg (n = 6): 1 year OS rate = 100%, median OS non recordable; concurrent NIVO + IPI (n = 53): 1 year OS rate = 82%, median OS = 39.7 months; sequenced regimen (NIVO + IPI followed by monotherapy with NIVO Q2W for 48 doses, n = 32): median OS = 13.0 months, insufficient follow-up of 1 year OS rate.

Subgroup analysis:

OR in PD-L1 positive tumors: concurrent therapy: 6 of 13 patients, sequential therapy: 4 of 8 patients;

OR in PD-L1 negative tumors: concurrent therapy: 9 of 22 patients; sequential therapy: 1 of 13 patients

NCT01024231 [54]

Advanced melanoma

Phase 1

Incidence of serious AE and treatment emergent AE; secondary outcomes: PFS, OS, ORR and duration of response (assessed up to week 49)

Arm 1: NIVO Q2W + TAK 580 QW; arm 2: plozalizumab 2 mg QW for weeks 1, 3, 5 and 9, then plozalizumab Q4W + NIVO Q2W; arm 3: IPI (once in week 3, 6, 9 and 12) + NIVO (administered in weeks 3, 6, 9, 12 and 15, Q2W thereafter) and vedolizumab (once in weeks 1, 3, 5 and 13)

Recruiting

NA

NCT02723006

Stage III unresectable or stage IV melanoma

Phase 1b

To determine MTD of specified treatment regimen (time frame: 12 months); secondary outcome: ORR

NIVO + IPI and ACY 241

Recruiting

NA

NCT02935790

BRAF mutant metastatic/unresectable melanoma

Phase 1 RCT

Incidence of AE (≥ grade 3 NCI CTCAE v4.0) evaluated up to 3 weeks after induction therapy with IPI; secondary outcomes: disease control rate and RR evaluated till 4 weeks after completion of therapy; proportion of patients with ≥ grade 3 AE after progression of disease on IPI

Arm A1: trametinib QID + dabrafenib BID for the first 25 days, then 4 courses of IPI Q3W; arm A2: 25 days of trametinib QID + dabrafenib BID, then 4 courses of IPI + NIVO Q3W, maintenance with NIVO Q2W (42 courses); arm B1: 25 days of trametinib QID, then 4 courses of IPI Q3W; arm B2: 25 days of trametinib QID, then 4 courses of IPI + NIVO Q3W, maintenance with NIVO Q2W (42 courses); arm C1: dabrafenib BID for 25 days, then 4 courses of IPI Q3W; arm C2: 25 days of dabrafenib BID, then 4 courses of IPI + NIVO Q3W, maintenance with NIVO Q2W (42 courses); arm D1: 4 courses of IPI Q3W; arm D2: 4 courses of IPI + NIVO Q3W, maintenance with NIVO Q2W (42 courses)

Recruiting

NA

NCT01940809

Stage IIIC/IV skin melanoma

Phase 1/Phase 2

Assess the safety of adjuvant NIVO + low-dose IPI

Low fixed dose NIVO in combination with low fixed dose IPI

Recruiting

NA

NCT02941744

Uveal melanoma with liver metastases

Phase 1/Phase 2

Evaluate tolerance and safety profile for treatment regimen (time frame: 3 years); secondary outcomes: PFS and RR (as per RECIST criteria)

Yttrium 90 followed by 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q3W; maintenance with NIVO 3 mg/kg monotherapy Q2W for a maximum of 3 years

Not yet recruiting

NA

NCT02913417

Metastatic melanoma

Phase 1/ Phase 2 RCT

Evaluation of grade 3–4 toxicity (treatment associated) event-free survival for up to 6 months

Active comparator: 4 doses of NIVO 1 mg/kg IV + IPI 3 mg/kg IV Q3W, then monotherapy with NIVO 3 mg/kg Q2W; experimental arm: 4 doses of NIVO 1 mg/kg IV + IPI 0.3 mg/kg IT Q3W, followed by monotherapy with NIVO 3 mg/kg Q2W

Recruiting

NA

NCT02857569 (NIVIPIT)

Recurrent/advanced melanoma

Phase 1/Phase 2 RCT

Pathological complete RR; secondary outcome: ORR, PFS (time frame: 5 years)

Arm A: 3 doses of NIVO 3 mg/kg Q2W, then surgery at weeks 6 to 8; maintenance with NIVO 3 mg/kg Q3W after surgery; Arm B: 2 doses of IPI 3 mg/kg + NIVO 1 mg/kg Q3W and then surgery; maintenance with 2 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q3W, continued as NIVO 3 mg/kg at Q3W

Recruiting

NA

NCT02736123

Advanced melanoma/renal cell carcinoma

Phase 1/ Phase 2 RCT

PFS, the number of study participants with AE (evaluation for up to 2 years), those discontinuing of study due to AE (evaluation for up to 2 years) and the patients that experienced DLT (assessed up to 6 weeks); secondary outcomes: OS, duration of response and ORR for phase 1b and 2

Arm 1: PEMBRO monotherapy; arm 2: two 6-weeks cycles of PEMBRO + IPI Q3W; arm 3: pegIFN-2b QW for each cycle (cycle duration: 6 weeks) + PEMBRO Q3W

Completed

(October 17, 2016 cut-off date): 153 participants received a minimum of 1 dose of PEMBRO + IPI; 72% (110 of 153 patients) received all 4 doses of PMEBRO + IPI; 42% (64 of 153 patients) were on PEMBRO monotherapy;

- TRAEs: 45% (69 of 153 patients) developed grade 3–4 TRAEs, 51% (78 of 153 patients) developed grade 1–2 TRAEs; irAEs: seen in 60% (92 of 153) participants, 27% (42 of 153 patients) documented to have grade 3–4 irAEs

OR: 61% (93 of 153 patients, 95%CI: 53–69)

- CR: 15% (23 of 153 patients)

- PR: 46% (70 of 153 patients)

- SD: 18% (28 of 153 patients)

- PD: 19% (29 of 153 patients)

- PFS at 12 months: 69% (95%CI: 60–75)

NCT02089685; KEYNOTE-029 [58]

Melanoma with leptomeningeal metastases

Phase 2

OS rate assessed at 2 years

Pre-determined doses of IPI + NIVO combination therapy, then monotherapy with NIVO, duration of each treatment cycle to be 6 weeks

Not yet recruiting

NA

NCT02939300

Resected stage IIIB/IIIC/IV melanoma

Phase 2

Evaluation of adverse effects with specified treatment regimen; secondary outcomes: time to relapse and immunological response

Cycle 1: 4 doses of IPI 1 mg/kg + NIVO 3 mg/kg Q3W for 12 weeks; cycles 2, 3, 4 and 5: monotherapy with NIVO 480 mg Q4W for 48 weeks

Not yet recruiting

NA

NCT02970981

Stage III/resected stage IV melanoma

Phase 2

Recurrence free survival and OS; evaluate toxicity of adjuvant low-dose IPI and NIVO for up to 7 months

Adjuvant therapy with NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W, for a total of 6 months duration

Recruiting

NA

NCT02656706; BrUOG 324

Uveal melanoma

Phase 2

OS at 12 months

4 doses of IPI + NIVO Q3W, then NIVO monotherapy Q2W

Recruiting

NA

NCT02626962; GEM1402

Uveal melanoma

Phase 2

ORR at 12 weeks

Induction phase: 4 doses of IPI 3 mg/kg + NIVO 1 mg/kg at week 1, 4, 7 and 10, continued through week 12; maintenance phase: monotherapy with NIVO 3 mg/kg Q2W for study participants with unmanageable toxicity or no progression after 12 weeks of induction therapy, to be continued till progression or unacceptable toxicity

Recruiting

NA

NCT01585194

Advanced melanoma

Phase 2

RR, evaluated up to 16 weeks; secondary outcomes: PFS assessed up to 24 months and safety

IPI + PEMBRO (all study participants to have received initial PD-1/PD-L1 antibody therapy prior to enrollment as per selection criteria)

Recruiting

NA

NCT02743819

Advanced mucosal/acral lentiginous melanoma

Phase 2

OR rate for mucosal melanoma (assessed up to 2 years); secondary outcomes: OR rate for acral lentiginous melanoma, PFS, OS

Induction phase: 4 doses of IPI 3 mg/kg + NIVO 1 mg/kg Q3W; maintenance phase: monotherapy with NIVO 3 mg/kg Q2W for 48 doses; NIVO monotherapy to be continued for another 12 weeks in study participants demonstrating CR

Not yet recruiting

NA

NCT02978443

Melanoma

Phase 2

Evaluation of clinical benefit rate up to 6 months

Induction: IPI + NIVO; maintenance phase: NIVO only

Recruiting

NA

NCT02320058; CheckMate 204

Advanced melanoma/bladder cancer

Phase 2

Evaluation of RR up to 12 weeks

Treatment regimen for melanoma patients: 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q2W

Recruiting

NA

NCT02553642

Stage III/IV melanoma with progression/relapse on PD-1 inhibitor therapy

Phase 2 RCT

Pathological CR with neoadjuvant IPI + NIVO combination therapy and neoadjuvant NIVO monotherapy, assessed at day 57

Group A: Neoadjuvant therapy with NIVO 3 mg/kg on weeks 1, 3, 5 and 7, then surgical excision, later adjuvant phase with NIVO 3 mg/kg Q2W for 6 months; group B: neoadjuvant therapy with IPI 3 mg/kg and NIVO 1 mg/kg on weeks 1, 4 and 7, then surgical excision and later adjuvant therapy same as group A

Recruiting

NA

NCT02519322

Stage III/IV melanoma with progression/relapse on PD-1 inhibitor therapy

Phase 2 RCT

OR as per RECIST v1.1 (time frame: 18 weeks)

Experimental arm 1: 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q3W; experimental arm 2: 4 doses of IPI 3 mg/kg monotherapy Q3W

Recruiting

NA

NCT02731729

Melanoma with brain metastases

Phase 2 RCT

Intracranial response rate assessed for up to 3 years; secondary outcomes: ORR, PFS, OS, extracranial response

Cohort 1: monotherapy with NIVO 3 mg/kg Q2W; cohort 2: monotherapy with NIVO 3 mg/kg Q2W; cohort 3: 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q3W, followed by NIVO 3 mg/kg Q2W

Recruiting

NA

NCT02374242

Stage III melanoma

Phase 2 RCT

Pathological response rate at 6 weeks; RR (assessed up to 6 weeks); incidence of treatment related AE (time frame: 12 weeks)

Arm A: 2 cycles of NIVO 1 mg/kg + IPI 3 mg/kg before surgery at week 6; arm B: 2 cycles of NIVO 3 mg/kg + IPI 1 mg/kg before surgery at week 6; arm C: 2 cycles of NIVO 3 mg/kg + IPI 3 mg/kg before surgery at week 6

Recruiting

NA

NCT02977052

Advanced/metastatic melanoma

Phase 2 RCT

Determining the percent candidates that develop grade 3–5 AE attributable to induction therapy (time frame: 25 weeks); secondary outcomes: investigator assessed duration of response, RR and rate of progression

Cohort A: NIVO preceding IPI: induction with 6 doses of NIVO 3 mg/kg IV Q2W, to be continued in maintenance phase for up to 2 years; 4 doses of IPI 3 mg/kg Q3W in induction phase only; Cohort B: IPI preceding NIVO: 4 doses of IPI 3 mg/kg Q3W in induction phase only; 6 doses of NIVO 3 mg/kg IV Q2W during induction, continued in maintenance phase for up to 2 years

Results available

- Grade 3–5 TRAEs

Cohort A: 34 of 68 patients (95%CI: 37.6–62.4); Cohort B: 30 of 70 patients (95%CI: 31.1–55.3)

- Response at 25 weeks:

Cohort A: 41% (28 patients, 95%CI: 29.4–53.8); Cohort B: 20% (14 patients, 95%CI: 11.4–31.3)

- 12 months OS:

Cohort A: 76% (95%CI: 64–85) Cohort B: 54% (95%CI: 42–65)

NCT01783938; CheckMate 064 [57]

Previously untreated unresectable/metastatic melanoma

Phase 2 RCT

Percent study participants (BRAF wild-type) with OR (time frame: 6 months or more)

Experimental regimen 1: 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q3W followed by monotherapy with NIVO 3 mg/kg Q2W; experimental regimen 2: placebo + 4 doses of IPI 3 mg/kg Q3W followed by placebo Q2W

Completed, results available

Participants with BRAF wild-type tumors: OR and CR with placebo: 11% (4 of 37 patients, 95%CI: 3 to 25) and 0%, respectively; OR and CR with combination therapy: 61% (44 of 72 patients, 95%CI: 49 to 72) and 22% (16 patients), respectively; HR = 0.40 (95%CI: 0.23 to 0.68, p < 0.001) for death or progression of disease when comparing IPI + NIVO combination therapy versus IPI + placebo.

Participants with BRAF mutant tumors: OR and CR with placebo: 10% (1 of 10 patients, 95%CI: 0 to 45) and 0%, respectively; OR and CR with combination therapy: 52% (12 of 23 patients, 95%CI: 31 to 73) and 22% (5 patients), respectively; HR = 0.38 (95%CI: 0.15 to 1.00);

Subgroup analysis: OR rate with combination therapy: PD-L1 positive tumors: 58, 95%CI: 37 to 78, PD-L1 negative tumors: 55, 95%CI: 41 to 69); OR with IPI monotherapy: PD-L1 positive tumors: 18% (95%CI: 2 to 52), PD-L1 negative tumors: 4% (95%CI: 0 to 19)

NCT01927419; CheckMate 069 [53]

Melanoma

Phase 2 RCT

Evaluation of the best ORR at 18 weeks; secondary outcomes: OS and PFS

Experimental arm: induction with cobimetinib + vemurafenib for 6 weeks followed by NIVO + IPI; Control arm: NIVO + IPI only

Not yet recruiting

NA

NCT02968303

BRAF mutant metastatic melanoma

Phase 2 RCT

OS evaluated up to 24 months; secondary outcomes: PFS (time frame: 2 years), 3 year PFS rate, duration of response (evaluated for 24 months)

Arm A: binimetinib 45 mg BID + encorafenib 450 mg OD till progression, then 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q3W and later NIVO 3 mg/kg Q2W; arm B: 4 doses of IPI 3 mg/kg + NIVO 1 mg/kg Q3W, later NIVO 3 mg/kg Q2W till disease progression, binimetinib 45 mg BID + encorafenib 450 mg OD till progression; arm C: binimetinib 45 mg BID + encorafenib 450 mg OD for 8 weeks, then 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q3W and later NIVO 3 mg/kg Q2W till progression. Thereafter, treatment continued with binimetinib 45 mg BID + encorafenib 450 mg OD till progression of disease

Recruiting

NA

NCT02631447; SECOMBIT study

Malignant melanoma

Phase 2 RCT

Evaluation of efficacy with adjuvant therapy with NIVO + IPI or NIVO monotherapy (time frame: 24 months)

Active comparator: Placebo + NIVO: IPI substituted with placebo for weeks 1, 4, 7 and 10; NIVO substituted with placebo for weeks 4 and 10; Experimental regimen: 4 doses of IPI 3 mg/kg + NIVO 1 mg/kg Q3W, placebo to replace NIVO on weeks 3, 5, 9 and 11, monotherapy with NIVO 3 mg/kg Q2W to be continued during maintenance phase for 1 year after induction or disease progression

Recruiting

NA

NCT02523313

Treatment naïve unresectable/metastatic advanced melanoma

Phase 3

To determine the incidence of TRAE; Secondary outcomes: ORR and PFS (time frame: 20 weeks)

Arm 1: concomitant NIVO + IPI followed by monotherapy with NIVO; arm 2: sequential administration of NIVO and IPI, followed by monotherapy with NIVO

Recruiting

NA

NCT02905266

Stage III unresectable or stage IV melanoma

Phase 3

TRAE for up to 24 months; secondary outcomes: PFS (investigator assessed), OS, ORR

NIVO monotherapy or NIVO + IPI combination therapy

Recruiting

NA

NCT02599402; CheckMate 401

Stage III/IV melanoma

Phase 3 RCT

OS rate at the end of 2 years follow-up; secondary outcomes: PFS and RR

Arm A: induction with 2 courses of NIVO + IPI Q6W, maintenance with NIVO monotherapy Q6W for a total of 12 courses, patients cross over to arm C if disease progresses; arm D: induction with 2 courses of NIVO + IPI Q6W, maintenance with NIVO monotherapy Q6W for a total of 12 courses

Recruiting

NA

NCT02224781

Treatment naïve unresectable/metastatic advanced melanoma

Phase 3 RCT

To determine the incidence of TRAE; Secondary outcomes: ORR, PFS, OS

Arm 1: IPI 1 mg/kg + NIVO 3 mg/kg; arm 2: IPI 1 mg/kg + NIVO 6 mg/kg; arm 3: IPI 3 mg/kg + NIVO 1 mg/kg

Recruiting

NA

NCT02714218

Treatment naïve unresectable/metastatic advanced melanoma

Phase 3 RCT

OS (time frame: 44.1 months), PFS (time frame: up to 5 years)

Arm A: NIVO 3 mg/kg Q2W + placebo substituting IPI on weeks 1 and 4, followed by placebo substituting NIVO on week 4 for cycle 1 and 2; Arm B: 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q3W followed by NIVO 3 mg/kg Q2W (placebo substituting NIVO on 3rd and 5th weeks for cycle 1 and 2; Arm C: 4 doses of IPI 3 mg/kg Q3W + placebo (replacing NIVO on 3rd and 5th weeks for cycles 1 and 2)

Completed, results available

OR: NIVO+IPI 58%, NIVO mono 44%, IPI mono 19%; CR: NIVO+IPI 19%, NIVO mono 16%, IPI mono 5%; Median PFS: NIVO monotherapy: 6.9 months (95%CI: 4.3 to 9.5), IPI monotherapy: 2.9 months (95%CI: 2.8 to 3.4) and IPI + NIVO: 11.5 months (95%CI: 8.9 to 16.7); median PFS for participants with PD-L1 positive malignancy: 14.0 months in NIVO arm and combination therapy arm; median PFS for participants with PD-L1 negative malignancy: 5.3 months (95%CI: 2.8 to 7.1) for NIVO monotherapy and 11.2 months (95%CI: 8.0 - not reached) for IPI + NIVO;

OS at 2 years: NIVO+ IPI 64%, NIVO monotherapy 59% and IPI monotherapy 45%; OS at 3 years: NIVO+ IPI 58%, NIVO monotherapy 52% and IPI monotherapy 34%; median OS NIVO+ IPI-not reached (95%CI 38.2 months - not reached), NIVO monotherapy-37.6 months (95%CI: 29.1 - not reached) and IPI monotherapy-19.9 months (95%CI: 16.9–24.9);

Grade 3–4 TRAEs: NIVO+IPI 59%, NIVO mono 21%, IPI mono 28%

NCT01844505; CheckMate 067 [56]