Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma

Daratumumab, a human CD38 IgG1κ monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose-escalation) evaluated 4 daratumumab doses plus lenalidomide (25 mg/day p.o. on Days 1 21 of each cycle) and dexamethasone (40 mg/week). Part 2 (dose-expansion) evaluated daratumumab at the recommended phase 2 dose (RP2D) plus lenalidomide/dexamethasone. Safety, efficacy, pharmacokinetics, immunogenicity and accelerated daratumumab infusions were studied. In Part 1 (13 patients), no dose-limiting toxicities were observed; 16 mg/kg was selected as the R2PD. In Part 2 (32 patients), median time since diagnosis was 3.2 years, with a median (range) of two (one-three) prior therapies, including proteasome inhibitors (91%), alkylating agents (91%), autologous stem cell transplant (78%), thalidomide (44%), and lenalidomide (34%); 22% were refractory to last line of therapy. Grade 3/4 adverse events (≥5%) included neutropenia, thrombocytopenia, and anemia. In Part 2, infusion-related reactions (IRRs) occurred in 18 patients (56%); most were grade ≤2 (grade 3, 6.3%). IRRs predominantly occurred during first infusions and were more common during accelerated infusions. In Part 2 (median follow-up of 15.6 months), overall response rate was 81% with 8 (25%) stringent complete responses, 3 (9%) complete responses, and 9 (28%) very good partial responses. Eighteen-month progression-free and overall survival rates were 72% (95% CI, 51.7-85.0) and 90% (95% CI, 73.1-96.8), respectively. Daratumumab plus lenalidomide/dexamethasone resulted in rapid, deep, durable responses. The combination was well-tolerated and consistent with the safety profiles observed with lenalidomide/dexamethasone or daratumumab monotherapy

Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma

Daratumumab, a human CD38 IgG1κ monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose-escalation) evaluated 4 daratumumab doses plus lenalidomide (25 mg/day p.o. on Days 1 21 of each cycle) and dexamethasone (40 mg/week). Part 2 (dose-expansion) evaluated daratumumab at the recommended phase 2 dose (RP2D) plus lenalidomide/dexamethasone. Safety, efficacy, pharmacokinetics, immunogenicity and accelerated daratumumab infusions were studied. In Part 1 (13 patients), no dose-limiting toxicities were observed; 16 mg/kg was selected as the R2PD. In Part 2 (32 patients), median time since diagnosis was 3.2 years, with a median (range) of two (one-three) prior therapies, including proteasome inhibitors (91%), alkylating agents (91%), autologous stem cell transplant (78%), thalidomide (44%), and lenalidomide (34%); 22% were refractory to last line of therapy. Grade 3/4 adverse events (≥5%) included neutropenia, thrombocytopenia, and anemia. In Part 2, infusion-related reactions (IRRs) occurred in 18 patients (56%); most were grade ≤2 (grade 3, 6.3%). IRRs predominantly occurred during first infusions and were more common during accelerated infusions. In Part 2 (median follow-up of 15.6 months), overall response rate was 81% with 8 (25%) stringent complete responses, 3 (9%) complete responses, and 9 (28%) very good partial responses. Eighteen-month progression-free and overall survival rates were 72% (95% CI, 51.7-85.0) and 90% (95% CI, 73.1-96.8), respectively. Daratumumab plus lenalidomide/dexamethasone resulted in rapid, deep, durable responses. The combination was well-tolerated and consistent with the safety profiles observed with lenalidomide/dexamethasone or daratumumab monotherapy

Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial

Background: Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profile in studies of phase 1 and 2 in patients with BRAF(V600)-mutated metastatic melanoma. We studied the efficacy of dabrafenib in patients with BRAF(V600E)-mutated metastatic melanoma. Methods: We enrolled patients in this open-label phase 3 trial between Dec 23, 2010, and Sept 1, 2011. This report is based on a data cutoff date of Dec 19, 2011. Patients aged 18 years or older with previously untreated, stage IV or unresectable stage III BRAF(V600E) mutation-positive melanoma were randomly assigned (3:1) to receive dabrafenib (150 mg twice daily, orally) or dacarbazine (1000 mg/m(2) intravenously every 3 weeks). Patients were stratified according to American Joint Committee on Cancer stage (unresectable III+IVM1a+IVM1b vs IVM1c). The primary endpoint was investigator-assessed progression-free survival and was analysed by intention to treat; safety was assessed per protocol. This study is registered with ClinicalTrials.gov, number NCT01227889. Findings: Of the 733 patients screened, 250 were randomly assigned to receive either dabrafenib (187 patients) or dacarbazine (63 patients). Median progression-free survival was 5·1 months for dabrafenib and 2·7 months for dacarbazine, with a hazard ratio (HR) of 0·30 (95% CI 0·18-0·51; p<0·0001). At data cutoff, 107 (57%) patients in the dabrafenib group and 14 (22%) in the dacarbazine group remained on randomised treatment. Treatment-related adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 patients who received dabrafenib and in 26 (44%) of the 59 patients who received dacarbazine. The most common adverse events with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and headache. The most common adverse events with dacarbazine were nausea, vomiting, neutropenia, fatigue, and asthenia. Grade 3-4 adverse events were uncommon in both groups. Interpretation: Dabrafenib significantly improved progression-free survival compared with dacarbazine

Articles Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial

Summary Background Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profi le in studies of phase 1 and 2 in patients with BRAF V600 -mutated metastatic melanoma. We studied the effi cacy of dabrafenib in patients with BRAF V600E -mutated metastatic melanoma