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Chronic Lymphocytic Leukemia

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June 16, 2014

AbbVie issued results of phase Ib trials of ABT-199/GDC-0199 in combination with rituximab for relapsed/refractory chronic lymphocytic leukemia (CLL) and various subtypes of non-Hodgkin’s lymphoma (NHL). The phase I, open-label, multicenter, international trial of ABT-199/GDC-0199 in patients with relapsed/refractory CLL and NHL enrolled 78 patients in the CLL arm and 62 patients in the NHL arm of the trial. In the CLL arm, due to concerns of TLS, the initial dose was reduced from 50mg to 20mg and daily dosing was modified to a weekly rampup period to the final dose of 400mg. A ramp-up period with weekly dose increases occurred from 20mg, 50mg, 100mg, 200mg to the final recommended phase II dose (RPTD) of 400mg. The overall response rate (ORR) was 77%, with 23% achieving complete response (CR). Of the 18 CR/CRi patients (complete response with incomplete blood count recovery), 11 were evaluated for minimal residual disease (MRD) and six were found to be MRD negative. The ORR for patients with 17p deletion and F-refractory CLL was 79% and 76%, respectively. ABT- 199/GDC-0199 as a monotherapy in patients with relapsed/refractory CLL harboring the 17p deletion is under investigation in an ongoing phase II clinical trial.

April 28, 2014

GlaxoSmithKline and Genmab released results of a phase III study of Arzerra (ofatumumab), in combination with chlorambucil for previously untreated patients with chronic lymphocytic leukemia (CLL). Results from the randomized, open-label, parallel-arm, pivotal phase III study evaluating the combination of ofatumumab and chlorambucil (N=221) v. chlorambucil alone (N=226) demonstrated statistically significant improvement in median PFS in patients randomized to ofatumumab and chlorambucil compared to patients randomized to chlorambucil alone (22.4 months v. 13.1 months, respectively) (HR=0.57 [95% CI, 0.45, 0.72] <0.001). The majority of adverse reactions (ARs) were Grade 2 or lower in both treatment arms. The most common (>/=5% in the ofatumumab plus chlorambucil arm and also >/=2% more than in the chlorambucil monotherapy arm) non-infusion-related ARs (all grades) as reported by investigators within 60 days following the last treatment were neutropaenia (27% ofatumumab + chlorambucil, 18% chlorambucil), asthaenia (8%, 5%), headache (7%, 3%), leukopaenia (6%, 2%), herpes simplex (6%, 4%), lower respiratory tract infection (5%, 3%), arthralgia (5%, 3%) and upper abdominal pain (5%, 3%).

April 15, 2013

Pharmacyclics reported results from a phase II trial of ibrutinib for relapsed and refractory chronic lymphocytic leukemia (CLL). This study enrolled 53 subjects with CLL, 24 who were treatment naïve and 29 who had a deletion of chromosome 17p. Subjects received ibrutinib for six months. Results showed ibrutinib demonstrated rapid and sustained disease control in blood, lymph nodes, spleen and bone marrow. After six months, 95% of patients experienced a reduction in lymph node size and all showed reduction in spleen enlargement, with a median reduction of 55%. In 26 patients, for whom a bone marrow biopsy was done, tumor infiltration decreased by 82%. The Progression Free Survival probability for these patients at 12 months was estimated to be 94%. Ibrutinib was well tolerated. The most frequent adverse events were diarrhea, fatigue and rash. Based on this data, the FDA has designated ibrutinib as a Breakthrough Therapy in CLL patients with deletion 17p.

November 12, 2012

MorphoSys and Xencor released results from a phase I/IIa trial of MOR208 (MOR00208/XmAb5574) for the treatment of tumor activity. This dose-ranging study enrolled patients with high-risk, heavily pretreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Subjects received doses ranging from MOR208 0.3mg/kg to 12mg/kg as an intravenous infusion on days 1, 4, 8, 15 and 22 in cycle one, and on days 1, 8, 15 and 22 in cycle two. Overall response rate by International Working Group on CLL (IWCLL) 2008 criteria was 11%, which utilizes more rigorous CT scan reduction of internal lymph nodes not previously required in older historic studies. Using IWCLL 1996 response criteria resulted in a response rate of 42%. MORE208 was well tolerated and found safe. The most frequent adverse events were mild to moderate infusion reactions usually with the first dose. Based on these results, MorphoSys plans to commence phase II studies of MOR208 in B-cell malignancies in the near future.

December 14, 2009

Roche reported positive long-term results from a phase III trial of Rituxan plus fludarabine and cyclophosphamide chemotherapy for the treatment of Chronic Lymphocytic Leukemia (CLL). This randomized study, dubbed CLL8, enrolled 817 subjects with previously untreated CD20-positive CLL. The subjects received fludarabine and cyclophosphamide chemotherapy alone at standard doses (FC arm) or FC plus rituximab, administered intravenously at 375 mg/m2 on day 0 at the first cycle and 500 mg/m2 on day 1 for all subsequent cycles, every 28 days (FCR arm). Three-year follow up data showed that 87.2% of subjects in the FCR arm were still alive after more than three years (37.7 months) compared to 82.5% of the FC alone treatment arm (p≡0.012). The median survival has not yet been reached. In addition, at this time point (37.7 months), subjects in the FCR arm had a median progression-free survival of 51.8 months compared to 32.8 months for those who received FC alone (p<0.001).

October 5, 2009

Genzyme issued positive interim results from a phase III trial of Campath for the treatment of chronic lymphocytic leukemia (CLL). This multicenter, international, open-label, randomized study, dubbed CAM314, enrolled 335 subjects with progressive Rai stage I-IV CLL. The trial was designed to compare Campath plus Fludara (FluCAM) to Fludara alone in terms of progression free survival. In the FluCAM arm, subjects received Campath in escalating doses of 3, 10, 30 mg IV (days 1-3 up to 14 days). They then received Fludara at 30 mg/m2 IV (days 1-3) followed by Campath 30 mg IV (days 1-3) every 28 days for up to 6 cycles. Subjects in the Fludara arm received Fludara at 25 mg/m2 IV daily for 5 consecutive days (days 1-5) every 28 days for up to 6 cycles. Treatment with FluCAM resulted in a significant increase in progression free survival versus Fludara alone (p<0.0173).

January 7, 2008

Cephalon reported positive results from a phase III trial of Treanda for the treatment of chronic lymphocytic leukemia (CLL). This randomized, international, multicenter, open-label study enrolled three-hundred and five subjects. It was designed to compare Treanda to chlorambucil. The subjects received Treanda (100 mg /M2 on days one and two) or chlorambucil (0.8 mg/kg on days one and fifteen) for up to six treatment cycles. The co-primary endpoints, overall response rate and progression-free survival, were both achieved. Overall response rate was significantly higher with Treanda than with chlorambucil (68% versus 39%; p<0.0001) with a strong complete response rate of 30% compared to 2%, a nodular partial response of 10% compared to 3%, and a partial response of 28% compared to 34%, respectively. Treanda significantly improved progression-free survival compared to chlorambucil (median 21.7 months versus 9.3 months, respectively; p<.0001). The median duration of response in the Treanda arm was 18.9 months compared to 6.1 months in the chlorambucil arm. An NDA is currently under review by the FDA.

Gloucester reported positive preliminary results from a phase II trial of romidepsin for the treatment of cutaneous t-cell lymphoma (CTCL) at the American Society of Hematology (ASH) Annual Meeting. Subjects enrolled in this non-randomized, open-label, single-arm international study received romidepsin at a dose of 14 mg/m(2), intravenously over four hours, on days one, eight and fifteen of a twenty-eight day cycle. The duration was six cycles, although those subjects who had an objective response or stable disease were eligible to continue therapy until disease progression. Of seventy- three evaluable subjects, an overall response rate of 37% was reported, with four complete responses, twenty-three partial responses and forty reports of stable disease. Six subjects had progressive disease. Of the subjects with severe pruritus at baseline, 37% reported significant relief. In addition, 38% of the subjects who exhibited any pruritus at baseline reported significant relief from symptoms. Treatment was determined to be safe and well tolerated. Based on the results, this phase II trial continues as planned.

Medarex and Bristol-Myers Squibb announced mixed top-line results from three phase III registrational trials (008, 022, 007) evaluating ipilimumab monotherapy for the treatment of metastatic melanoma. These international trials included an open-label, single arm trial (008) evaluating overall response rate in one hundred and fifty-five subjects who progressed on or following standard treatment; a randomized, double-blind trial (022) evaluating the efficacy of three dose levels of ipilimumab in two hundred and sixteen subjects who were previously treated, relapsed or failed to respond to experimental treatment or were unable to tolerate currently approved therapies; and a randomized, double-blind, placebo-controlled trial (007) in one-hundred and sixteen subjects comparing the safety of ipilimumab, with or without prophylactic oral budesonide (primarily evaluating the rate of grade 2+ diarrhea). The results from study 008, conducted under a SPA, did not meet the primary endpoint, which was to rule out a best objective response rate of less than ten percent. However, the totality of data from the trials included a clear dose response effect observed in study 022 and best objective response rates across the three studies ranging from mid-single digits to mid-teens as determined by independent radiology review. The objective responses included complete and partial responses. Medarex and BMS were planning to meet with the regulatory authorities and file for US approval by the first half of 2008.

October 1, 2007

Celgene released positive results from two ongoing phase II trials of Revlimid for the treatment of Chronic Lymphocytic Leukemia (CLL) at the 12th International Workshop on Chronic Lymphocytic Leukemia. The first trial enrolled 45 CLL subjects who had at least two prior therapies. The subjects received 25 mg of Revlimid orally once daily for 21 days in a four-week cycle. The overall response rate was 58%, of whom 18% achieved a complete remission and 40% partial remission. The median time to best response was 5.9 months and the median progression free survival was 19.4 months. Of subjects with poor prognostic factors, 44% showed a clinical response, while 30% of those with fludarabine refractory disease showed a clinical response. Treatment was generally well tolerated, with no unexpected adverse events. The second trial enrolled 44 subjects with CLL who had received prior purine analog-based combinations. Revlimid 10 mg orally once daily was administered for four weeks, followed by dose escalation by 5 mg every 28 days to a maximum dose of 25mg/day. The overall response rate was 34%, among which 7% achieved a complete remission, 2% achieved a nodular partial remission and 25% achieved a partial remission. Stable disease was observed in 23% of the subjects. The median response duration to date is 12-plus months. Based on the results, Celgene plans to move forward with the development of Revlimid for the treatment of CLL.