A phase I/II study of the selective phosphatidylinositol 3-kinase-delta (PI3Kδ) inhibitor, GS-1101 (CAL-101), with ofatumumab in patients with previously treated chronic lymphocytic leukemia (CLL).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6518-6518 ◽  
Author(s):  
Richard R. Furman ◽  
Jacqueline Claudia Barrientos ◽  
Jeff Porter Sharman ◽  
Sven De Vos ◽  
John Leonard ◽  
...  
Keyword(s):  
Treated Patient ◽  
Alkylating Agents ◽  
Phase 1 ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Combination Regimen ◽  
Highly Active ◽  
Previously Treated ◽  
Orally Bioavailable

6518^ Background: PI3Kδ is expressed in cells of hematopoietic origin where it regulates the survival and proliferation of malignant B-cells. GS-1101 is an orally bioavailable, small-molecule inhibitor that selectively targets PI3Kδ and is highly active in patients with hematologic malignancies. Methods: This Phase 1/2 study evaluated repeated 28-day cycles of GS‑1101 in combination with ofatumumab. GS-1101 (150mg BID) was co-administered with a total of 12 infusions of ofatumumab over 24 weeks (300mg initial dose either on Day 1 or Day 2 (relative to the first dose of GS-1101), followed 1 week later by 1,000mg weekly for 7 doses, followed 4 weeks later by 1,000mg every 4 weeks for 4 doses). Thereafter, each subjects received single-agent GS‑1101 as long as the subject was benefitting. Results: Accrual is complete with 21 subjects enrolled and 11 evaluable. Six subjects started ofatumumab treatment on Day 1 and 5 on Day 2. Median [range] age was 63 [54‑76] years. The majority (9/11; 82%) of patients had bulky adenopathy. The median [range] number of prior therapies was 3 [1‑6], including prior exposure to alkylating agents (10/11; 90%), rituximab (9/11; 82%), purine analogs (8/11; 72%), alemtuzumab (3/11; 28%) and/or ofatumumab (2/11;18%). At the data cutoff, the median [range] treatment duration was 5 [0‑7] cycles. Almost all subjects (9/11;82%) experienced marked and rapid reductions in lymphadenopathy within the first 2 cycles. The lymphocyte mobilization that is expected with PI3Kδ inhibition was significantly reduced in magnitude and duration and persisted past Cycle 1 in only 1 patient. Early follow up data support a favorable safety profile and confirm a lack of clinically significant myelosuppression. Elevated baseline levels of CCL3, CCL4, CXCL13, and TNFa were significantly reduced after 28 days of treatment. Conclusions: GS-1101/ofatumumab offers a well-tolerated noncytotoxic combination regimen with substantial activity in previously treated patient with bulky adenopathy. Data on the complete cohort of 21 subjects will be presented.

scholarly journals Relapsed CLL: sequencing, combinations, and novel agents

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 248-255 ◽  
Author(s):  
Jennifer R. Brown
Keyword(s):  
Kinase Inhibitor ◽  
Treated Patient ◽  
Phase 1 ◽  
Prospective Trial ◽  
Lymphocytic Leukemia ◽  
Novel Agents ◽  
Phosphatidylinositol 3 Kinase ◽  
Prognostic Features ◽  
Prior Therapy ◽  
Previously Treated

AbstractAlthough the therapy of chronic lymphocytic leukemia (CLL) has changed rapidly over the last 5 years, the key considerations in selecting a therapy for a previously treated patient with CLL continue to include the nature of the prior therapy and the duration of prior remission to that therapy, the prognostic features of the disease, and the health and comorbidities of the patient in question. For patients treated initially with chemoimmunotherapy, randomized trials have demonstrated the benefit of targeted therapy. Retrospective data suggest that ibrutinib is preferred as a first kinase inhibitor, whereas recent data with venetoclax and rituximab may challenge the choice of ibrutinib as a first novel agent in the relapsed setting. Data on sequencing of novel agents remain quite sparse, consisting of 1 prospective trial that demonstrated the efficacy of venetoclax in patients who have experienced progression with a kinase inhibitor, as well as a retrospective real-world analysis supporting this observation. Novel agents in advanced clinical development include primarily next-generation Bruton’s tyrosine kinase and phosphatidylinositol 3-kinase δ inhibitors, with other classes still in phase 1 trials. Clinical trials of combination time-limited therapies with the goal of deep remission and discontinuation are also in progress.

A Pilot Study of Genasense® (Oblimersen Sodium, Bcl-2 Antisense Oligonucleotide), Fludarabine and Rituximab in Previously Treated and Untreated Subjects with Chronic Lymphocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4827-4827 ◽  
Author(s):  
Asher Alban Chanan-Khan ◽  
Blanche Mavromatis ◽  
Kanti R. Rai ◽  
Philomena Casey ◽  
Steven Novick ◽  
...  
Keyword(s):  
Adverse Events ◽  
Lymphocyte Count ◽  
Alkylating Agents ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Serious Adverse Events ◽  
Reduced Dose ◽  
Previously Treated ◽  
Grade 3

Abstract Bcl-2 is an anti-apoptotic protein closely linked to chemotherapy resistance and inferior survival in patients (pts) with CLL. Genasense(GNS) enhances apoptosis induced by fludarabine (F), dexamethasone, and rituximab (R) in vitro, and has limited single-agent activity in heavily pre-treated CLL pts. Down-regulation of Bcl-2 may further sensitize CLL cells to apoptosis induced by F and R without exposing subjects to the toxicity of alkylating agents. CLL and NHL pts occasionally exhibit a “cytokine release syndrome” (spiking fever, back pain, and occasional hypotension) with GNS treatment. We hypothesized that a “step dosing” approach with GNS, similar to that sometimes used for R, could ameliorate these effects and allow safe and effective combination of this agent with F and R. We are currently evaluating this combination in pts with either previously untreated (UT) or relapsed, previously treated (PT) CLL who require systemic treatment. Eligibility includes: plts ≥ 50,000/mm3; serum Cr ≤ 1.5 mg/dL; adequate organ function; negative Coombs; no history of autoimmune hemolytic anemia. In cycle 1, GNS is given by continuous intravenous infusion at 1.5 mg/kg/d days 1 to 7. R is given on a dose-escalating schema (day 4, 125 mg/m2; day 6, 250 mg/m2). F (25 mg/m2/d) is given on days 6 to 8. In subsequent 28-day cycles (up to 6), the dose of GNS is escalated to 3 mg/kg/d days 1 to7 days, with R 375 mg/m2 on day 5 and F days 5 to7. To date, 20 pts have been enrolled (17 PT and 3 UT). Characteristics included: median age, 62 yrs (range 39 to 82 yrs); Rai stage III (2 pts) and IV (6 pts). Prior to administration of either F or R, single-agent GNS treatment at the initial reduced dose in Cycle 1 resulted in a median decrease in lymphocytes of 15% (among all patients regardless of decline in lymphocyte count) (Baseline: 48.3 cells x 103/ml; day 4: 40.1 cells x 103/ml). For the 13 pts who experienced a decline in lymphocyte count in cycle 1 prior to F and R, the median percentage change was 17%, with 4 pts having a > 25% decrease. Three PT pts discontinued from study treatment prior to completing 6 cycles, 2 due to disease progression, and 1 with Grade 3 thrombocytopenia that was unresolved after 4 weeks. Among the 20 pts treated to date (9 ongoing), the most common grade 3 or higher adverse events have been neutropenia, pyrexia and thrombocytopenia. Serious adverse events have been noted in only 6 of 20 pts (all PT pts) and have included 2 pts with fever (1 neutropenic), 2 R infusion reactions, 1 lymph node abscess and 1 tumor lysis syndrome (with sepsis). Conclusions: 20 pts have been treated with combination GNS, F and R. Single-agent activity with GNS has been observed at a reduced dose of 1.5 mg/kg/d in cycle 1. The “step dosing” approach appears to be a well-tolerated, alternative approach to the administration of GNS. Further details of safety and efficacy will be presented.

scholarly journals Long-term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 2878-2884 ◽  
Author(s):  
MJ Keating ◽  
S O'Brien ◽  
H Kantarjian ◽  
W Plunkett ◽  
E Estey ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Response ◽  
Alkylating Agents ◽  
Single Agent ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
Strongly Correlated ◽  
Prior Therapy ◽  
Previously Treated

Abstract The clinical response and survival of 113 patients with at least 3-year follow-up after treatment with fludarabine as a single agent for chronic lymphocytic leukemia has been evaluated. Seventy-eight patients were previously treated and 35 were untreated. The response to therapy and survival were strongly correlated with the degree of previous therapy, the stage of disease, and whether or not the patients were refractory to alkylating agents. Other characteristics associated with survival were the age of the patient and the serum albumin level at the start of therapy. The median time to progression of responders who had not received prior therapy was 33 months and was 21 months for previously treated patients. Survival after progression of disease was also strongly correlated with the degree of prior therapy. No successful salvage regimen after initial fludarabine therapy was shown for patients refractory to alkylating agents, although fludarabine achieved further remissions in patients who had received fludarabine as their initial treatment or were not refractory to alkylating agents. The morbidity of patients in unmaintained remission on discontinuation of fludarabine was low, with less than one episode of infection per patient-year at risk. The morbidity during this time was correlated with clinical response and whether the patients had received prior therapy. Although fludarabine is a very effective cytoreductive regimen, most patients, including those who achieved true complete remissions, will have recurrent disease. Longer follow-up and comparative trials are required before the effect of fludarabine on survival is shown.

Results of the Fludarabine and Cyclophosphamide Combination Regimen in Chronic Lymphocytic Leukemia

2001 ◽  
Vol 19 (5) ◽  
pp. 1414-1420 ◽  
Author(s):  
Susan M. O’Brien ◽  
Hagop M. Kantarjian ◽  
Jorge Cortes ◽  
Miloslav Beran ◽  
Charles A. Koller ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Alkylating Agents ◽  
Single Agent ◽  
Unknown Origin ◽  
Lymphocytic Leukemia ◽  
Combination Regimen ◽  
Synergistic Activity

PURPOSE: To assess the efficacy of combination therapy with fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia (CLL) based on data suggesting in vitro synergistic activity of the two agents. PATIENTS AND METHODS: A total of 128 patients with CLL were treated with fludarabine 30 mg/m2 intravenously daily for 3 days and cyclophosphamide at either 500 mg/m2 daily for 3 days (n = 11), 350 mg/m2/d for 3 days (n = 26), or 300 mg/m2 daily for 3 days (n = 91). The cyclophosphamide dose was decreased because of myelosuppression in the early part of the study. Patients were divided into four groups based on the expectation for response to single-agent fludarabine, including previously untreated patients, patients previously treated with alkylating agents, patients successfully treated with alkylating agents and fludarabine but relapsing, and patients refractory to fludarabine with or without alkylating agents. RESULTS: Fludarabine and cyclophosphamide produced ≥ 80% response rates in all patients not refractory to fludarabine at the start of therapy as well as a 38% response rate in patients who were refractory to fludarabine. The complete remission (CR) rate was 35% in previously untreated patients, which was not significantly different from the CR rate in historical control patients treated with single-agent fludarabine. However, residual disease assessed by flow cytometry occurred in only 8% of previously untreated patients achieving CR, and median time to progression has not been reached after a median follow-up of 41 months. The main complication of therapy was related to myelosuppression and infection. Neutropenia to less than 500 × 109/L was noted in 48% of patients who received cyclophosphamide 300 mg/m2. Pneumonia or sepsis occurred in 25% of patients, and fever of unknown origin occurred in another 25%. Pneumonia or sepsis were significantly more frequent in patients who were refractory to fludarabine at the start of combination chemotherapy. CONCLUSION: Fludarabine and cyclophosphamide seem to have a significant advantage over single-agent fludarabine in the salvage setting. Although the CR rate was not increased in previously untreated patients, residual disease detected by flow cytometry was rare and remission durations seemed to be prolonged in this subset. Myelosuppression and infection remain the most significant complications of therapy in CLL.

scholarly journals Long-term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 2878-2884 ◽  
Author(s):  
MJ Keating ◽  
S O'Brien ◽  
H Kantarjian ◽  
W Plunkett ◽  
E Estey ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Response ◽  
Alkylating Agents ◽  
Single Agent ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
Strongly Correlated ◽  
Prior Therapy ◽  
Previously Treated

The clinical response and survival of 113 patients with at least 3-year follow-up after treatment with fludarabine as a single agent for chronic lymphocytic leukemia has been evaluated. Seventy-eight patients were previously treated and 35 were untreated. The response to therapy and survival were strongly correlated with the degree of previous therapy, the stage of disease, and whether or not the patients were refractory to alkylating agents. Other characteristics associated with survival were the age of the patient and the serum albumin level at the start of therapy. The median time to progression of responders who had not received prior therapy was 33 months and was 21 months for previously treated patients. Survival after progression of disease was also strongly correlated with the degree of prior therapy. No successful salvage regimen after initial fludarabine therapy was shown for patients refractory to alkylating agents, although fludarabine achieved further remissions in patients who had received fludarabine as their initial treatment or were not refractory to alkylating agents. The morbidity of patients in unmaintained remission on discontinuation of fludarabine was low, with less than one episode of infection per patient-year at risk. The morbidity during this time was correlated with clinical response and whether the patients had received prior therapy. Although fludarabine is a very effective cytoreductive regimen, most patients, including those who achieved true complete remissions, will have recurrent disease. Longer follow-up and comparative trials are required before the effect of fludarabine on survival is shown.

Combinations of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3Kdelta) Inhibitor GS–1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL): Results From a Phase I Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 191-191 ◽  
Author(s):  
Steven E. Coutre ◽  
John P. Leonard ◽  
Richard R. Furman ◽  
Jacqueline C. Barrientos ◽  
Sven de Vos ◽  
...  
Keyword(s):  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Lymphocytic Leukemia ◽  
Tumor Control ◽  
Prior Therapy ◽  
Highly Active ◽  
Heavily Pretreated

Abstract Abstract 191 Introduction: PI3Kdelta drives proliferation and survival in malignant B-cells. GS-1101 is an orally bioavailable, small-molecule inhibitor of PI3Kdelta that has shown considerable monotherapy activity when given at dose levels of 3100 mg BID in patients with heavily pretreated CLL. Methods and Patients: This Phase 1 combination study has evaluated repeated 28-day cycles of GS-1101 in combination with rituximab and/or bendamustine in patients with previously treated CLL. GS-1101 was administered starting on Day 1 of Cycle 1 with rituximab (R) (375 mg/m2 given weekly for 8 doses) (GS-1101/R regimen), with bendamustine (B) (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles) (GS-1101/B regimen), or in combination with R (375 mg/m2, on Day 1 of each cycle for 6 cycles) and B (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles) (GS-1101/BR regimen). Initial cohorts of patients received a GS-1101 dose of 100 mg/dose BID in the GR or GB regimens. Thereafter, all patients received a GS-1101 dose of 150 mg/dose BID. Tumor response was evaluated according to standard criteria (Hallek 2008). Chemokine/cytokine plasma levels were assessed at baseline and on Day 28 of therapy using multiplexed bead suspension arrays. Results: The study enrolled a total of 51 patients with CLL. Patient characteristics and safety and efficacy results are depicted in the table The majority of patients had bulky adenopathy and had undergone extensive prior therapy, with virtually all patients receiving prior rituximab and many receiving prior bendamustine. Grade 33 adverse events and lab abnormalities were generally consistent with those expected with each of the single agents. Lymph node shrinkage was rapid, and almost all evaluable patients had reductions in lymphadenopathy. As reported by investigators, the overall response rates (ORR) for the GS-1101/R, GS-1101/B, and GS-1101/BR regimens were 78%, 82% and 87%, respectively. With a minimum follow-up of 340 weeks for all regimens, 1-year progression-free survival (PFS) rates were 74%, 88% and 87% in the GS-1101/R, GS-1101/B, and GS-1101/BR treatment groups, respectively. Disease-associated chemokines/cytokines were commonly elevated at baseline and were significantly reduced by GS-1101-based combination treatment. Conclusions: A favorable safety profile and lack of overlapping toxicities allows the oral PI3Kdelta inhibitor, GS-1101, to be delivered at the full single-agent starting dose when coadministered with chemoimmunotherapies in heavily pretreated patients with CLL. GS-1101-based combination therapies with rituximab and/or bendamustine offer major and rapid reductions in lymphadenopathy and durable tumor control. Based on these results, Phase 3 trials evaluating the efficacy of GS-1101 in combination with R or BR have been initiated (NCT01539512 [GS-1101/placebo+R], NCT01569295 [GS-1101/placebo+BR]). Disclosures: Coutre: Gilead: Consultancy. Off Label Use: Phase 1 trial of GS-1101 (CAL-101)-based combination therapy. Leonard:Gileade: Consultancy. Barrientos:Gilead: Research Funding. de Vos:Gilead: Consultancy. Sharman:Gilead: Honoraria, Research Funding. Holes:Gilead: Employment. Lannutti:Gilead Sciences Inc: Employment. Johnson:Gilead Sciences: Employment. Miller:Gilead: Employment. Jahn:Gilead: Employment.

A Phase 1 Study of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3Kδ) Inhibitor, CAL-101 (GS-1101), in Combination with Rituximab and/or Bendamustine in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1787-1787 ◽  
Author(s):  
Jeff Sharman ◽  
Sven de Vos ◽  
John P. Leonard ◽  
Richard R. Furman ◽  
Steven E. Coutre ◽  
...  
Keyword(s):  
Lymph Node ◽  
Combination Therapy ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Phase 1 Study ◽  
Starting Dose

Abstract Abstract 1787 Introduction: PI3Kδ is expressed in cells of hematopoietic origin where it regulates survival and proliferation of normal and malignant B-cells. CAL-101 (GS-1101) is an orally bioavailable, small-molecule inhibitor that selectively targets PI3Kδ. A prior Phase 1 study established 150 mg/dose BID as an appropriate single-agent starting dose for GS-1101 and demonstrated that GS-1101 monotherapy is associated with substantial clinical activity in patients with hematologic malignancies. Methods and Patients: This Phase 1 study has evaluated repeated 28-day cycles of GS-1101 in combination with rituximab and/or bendamustine in patients with previously treated CLL. GS-1101 (G) was administered starting on Day 1 of Cycle 1 with rituximab (R) (375 mg/m2 given weekly for 8 doses, GR regimen), with bendamustine (B) (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles, GB regimen), or in combination with R (375 mg/m2, on Day 1 of each cycle for 6 cycles) and B (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles, GRB regimen). Initial cohorts of patients received GS-1101 at a dose of 100 mg/dose BID in the GR or GB regimens. Thereafter, all patients received GS-1101 at a dose of 150 mg/dose BID in the GR, GB, or GRB regimens. Chemokine/cytokine plasma levels were assessed at baseline and on Day 28 of therapy using multiplexed bead suspension arrays. Tumor response was evaluated according to standard criteria (Hallek et al, 2008). Results: At data cutoff, the study had enrolled 27 patients with CLL. Patient characteristics and safety and efficacy results are depicted in the table. The majority of patients were >60 years of age, had bulky adenopathy, and had undergone extensive prior therapy. Grade ≥3 adverse events were generally consistent with those expected with each of the single agents. During combination therapy, the substantial majority of patients had marked reductions in lymphadenopathy, resulting in a ≥50% decrease in lymph node area in >75% of patients on all regimens. Lymph node shrinkage was rapid, generally occurring within ≤2 cycles. The lymphocyte mobilization that is expected with PI3Kδ inhibition was observed in some patients but was not as prominent as had previously been seen with single-agent GS-1101 therapy. More than 80% of patients receiving each regimen met criteria for CLL response. Disease-associated chemokines/cytokines were commonly elevated at baseline and were reduced by GS-1101 treatment; in 20 evaluable patients, mean (±SEM) values declined from 116 (±36) to 33 (±5.5) pg/mL for CCL3 (p=0.022), from 217 (±83) to 55 (± 28) pg/mL) for CCL4 (p=0.052), from 220 (± 57) to 46 (± 6.6) pg/mL for CXCL13 (p=0.004), and from 100 (± 20) to 30 (± 3.6) pg/mL for TNFα (p=0.001). Conclusions: A favorable safety profile and lack of overlapping toxicities allows the oral PI3Kδ inhibitor, CAL-101 (GS-1101), to be delivered at the full single-agent starting dose when coadministered with chemoimmunotherapies in heavily pretreated patients with CLL. GS-1101-based combination therapy with rituximab and/or bendamustine offers major and rapid reductions in lymphadenopathy. Patients with CLL are currently being enrolled in this study to receive GS-1101 with fludarabine or ofatumumab; data for all regimens will be presented. The data from this trial will be used to design Phase 3 combination studies of GS-1101 in patients with CLL. Disclosures: Sharman: calistoga: Honoraria; Pharmacyclics: Honoraria; Genentech: Honoraria; Rigel: Research Funding; Portola: Consultancy; Pharmacyclics: Consultancy; Gilead: Consultancy. de Vos:Gilead: Consultancy. Leonard:Gilead: Consultancy. Coutre:Gilead: Consultancy. Flinn:Gilead: Research Funding. Fowler:Gilead: Consultancy. Holes:Gilead: Employment. Lannutti:Gilead: Employment. Johnson:gILEAD: Employment. Jahn:gILEAD: Employment. Miller:Gilead: Employment.

A Phase 1 Study of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3Kδ) Inhibitor, Cal-101 (GS-1101), in Combination with Rituximab and/or Bendamustine in Patients with Previously Treated, Indolent Non-Hodgkin Lymphoma (iNHL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2699-2699 ◽  
Author(s):  
Sven de Vos ◽  
Marshall T. Schreeder ◽  
Ian W. Flinn ◽  
Steven E. Coutre ◽  
John P. Leonard ◽  
...  
Keyword(s):  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Patient Characteristics ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Phase 1 Study ◽  
Prior Therapy ◽  
Starting Dose ◽  
Previously Treated

Abstract Abstract 2699 Introduction: PI3Kδ is expressed in cells of hematopoietic origin where it regulates survival and proliferation of normal and malignant B-cells. CAL-101 (GS-1101) is an orally bioavailable, small-molecule inhibitor that selectively targets PI3Kδ. A prior Phase 1 study established 150 mg/dose BID as an appropriate single-agent starting dose for GS-1101 and demonstrated that GS-1101 monotherapy is associated with substantial clinical activity in patients with hematologic malignancies. Methods and Patients: This Phase 1 study has evaluated repeated 28-day cycles of GS-1101 in combination with rituximab and/or bendamustine in patients with previously treated iNHL. GS-1101 (G) was administered starting on Day 1 of Cycle 1 with rituximab (R) (375 mg/m2 given weekly for 8 doses, GR regimen), with bendamustine (B) (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles, GB regimen), or in combination with R (375 mg/m2, on Day 1 of each cycle for 6 cycles) and B (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles, GRB regimen). Initial cohorts of patients received GS-1101 at a dose of 100 mg/dose BID in the GR or GB regimens. Thereafter, all patients received GS-1101 at a dose of 150 mg/dose BID in the GR, GB, or GRB regimens. Chemokine/cytokine plasma levels were assessed at baseline and on Day 28 of therapy using multiplexed bead suspension arrays. Tumor response was evaluated according to standard criteria (Cheson et al. 2007). Results: At data cutoff, the study had enrolled 37 patients with iNHL. Patient characteristics, histological subtyping, safety, and efficacy results are depicted in the table. The majority of patients were >60 years of age and had undergone extensive prior therapy. Grade ≥3 adverse events were generally consistent with those expected with each of the single agents. All evaluable patients had reductions in lymphadenopathy, resulting in an overall response rate (ORR) of >65% for all regimens. In 3 patients among the 24 patients receiving either GB or GRB, 3 complete responses were observed. Lymph node shrinkage was rapid; responses generally occurred within ≤2 cycles. Disease-associated chemokines/cytokines were commonly elevated at baseline and were reduced by GS-1101 treatment; in 20 evaluable patients, mean (±SEM) values declined from 302 (±68) to 62 (±14) pg/mL for CCL17 (p=0.001), from 2512 (±332) to 879 (± 88) pg/mL) for CCL22 (p=0.0001), from 517 (± 88) to 107 (± 34) pg/mL for CXCL13 (p=0.0001), and from 33 (± 5.4) to 18 (± 1.8) pg/mL for TNFα (p=0.007). Conclusions: A favorable safety profile and lack of overlapping toxicities allows the oral PI3Kδ inhibitor, CAL-101 (GS-1101), to be delivered at the full single-agent starting dose when coadministered with chemoimmunotherapies in heavily pretreated patients with iNHL. GS-1101-based combination therapy with rituximab and/or bendamustine offers major and rapid reductions in lymphadenopathy. The data from this trial will be used to design Phase 3 combination studies of GS-1101 in patients with iNHL. Disclosures: de Vos: Gilead Sciences Inc: Consultancy. Flinn:Gilead Sciences Inc: Research Funding. Coutre:Gilead Sciences Inc: Consultancy. Leonard:Gilead Sciences Inc: Consultancy. Fowler:Gilead Sciences Inc: Consultancy. Sharman:calistoga: Honoraria; Pharmacyclics: Honoraria; Genentech: Honoraria; Rigel: Research Funding; Portola: Consultancy; Pharmacyclics: Consultancy; Gilead: Consultancy. Holes:Gilead: Employment. Lannutti:Gilead: Employment. Johnson:Gilead Sciences Inc: Employment. Jahn:gILEAD: Employment. Miller:Gilead: Employment.

Campath-1H and fludarabine in combination are highly active in refractory chronic lymphocytic leukemia

Blood ◽  
2002 ◽  
Vol 99 (6) ◽  
pp. 2245-2247 ◽  
Author(s):  
Ben Kennedy ◽  
Andy Rawstron ◽  
Chris Carter ◽  
Mary Ryan ◽  
Kevin Speed ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Chronic Lymphocytic Leukemia ◽  
Conventional Treatment ◽  
Single Agent ◽  
Complete Response ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Novel Therapy ◽  
Highly Active ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Campath-1H (alemtuzumab) is the most effective monoclonal antibody in single-agent use in B-cell chronic lymphocytic leukemia (CLL) with reported response rates of 33% to 70%. Combination therapy is now the conventional treatment for most hematologic malignancies. Monoclonal antibody treatments may sensitize tumor cells to subsequent chemotherapy. We report the combination of Campath-1H with fludarabine in patients with CLL refractory to each agent used singly. Six patients who had received a median of 8 courses of fludarabine (range, 4-10 courses) and 16 weeks of Campath-1H (range, 8-32 weeks) were treated. Five patients responded, including one who had a complete response by National Cancer Institute criteria. The responses observed were better in each patient than responses after each agent used singly. Complete morphologic bone marrow responses were seen in 3 patients, including eradication of disease measured by sensitive flow cytometry in 2. Campath-1H combined with fludarabine is a highly promising novel therapy for refractory CLL.

Phase 1/2 study of cirmtuzumab and ibrutinib in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7556-7556
Author(s):  
Hun Ju Lee ◽  
Michael Y. Choi ◽  
Tanya Siddiqi ◽  
Jacqueline Claudia Barrientos ◽  
William G. Wierda ◽  
...  
Keyword(s):  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Synergistic Activity ◽  
Best Response ◽  
Car T ◽  
Treatment Naïve

7556 Background: Cirmtuzumab (Cirm) is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and had demonstrated additive/synergistic activity with many anti-cancer agents including ibrutinib (Ibr). Methods: Patients (Pts) with relapsed or refractory (RR) MCL or treatment naïve (TN) or RR CLL were enrolled. In Part 1 (Dose Escalation), doses of Cirm IV q2wks x5 then q4wks of 2-16 mg/kg and 300 or 600 mg were examined. Safety of Cirm alone was assessed during the first 28 days, then Ibr was started at approved doses for each indication. Cirm 600 mg IV q2wks x3 then q4wks in combination with Ibr starting day 0 was chosen as the recommended dosing regimen for use in Part 2 (Expansion) and Part 3 (CLL only, Cirm/Ibr vs. Ibr alone). Results: Twelve evaluable MCL pts were enrolled into Part 1, and 5 into Part 2. Median number of prior regimens was 2 (1-5), including pts relapsing after Ibr (4), auto-SCT (3), auto-SCT/ allo-SCT (1), auto-SCT/CAR-T (1). In CLL, 34 evaluable pts (12 TN and 22 RR) enrolled into Part 1 (18) or Part 2 (16). At least 74% of CLL pts in Parts 1 and 2 were high risk as determined by unmutated IGHV, del17p, and/or del11q. In Part 3, 22 evaluable pts received Cirm/Ibr (15) or Ibr (7). As of the 30OCT2020 safety cut-off for MCL and CLL, common TEAEs (all grades) included diarrhea (41%), contusion (39%), fatigue (39%), URI (31%), hypertension (25%) arthralgia (23%). Grade ≥3 neutropenia was 13% and thrombocytopenia 1%. There were no Cirm dose reductions or discontinuations for toxicity. Overall, Cirm did not appear to negatively impact the safety of Ibr. Efficacy (MCL): As of the 02FEB2021 efficacy cutoff, the best response of 17 evaluable pts in Parts 1 and 2 included an objective response rate (ORR) of 82%, 41% CR/CMR, 41% PR, 12% SD, and 6% PD. CR/CMR remain durable from 8-28+ mos. Most responses occurred rapidly after ̃3 mos of Cirm/Ibr. Notably, responses were achieved in all pts who received prior SCT+/- CAR-T (4CR, 1PR) or prior Ibr (2CR, 2PR). At a median follow-up of 14.6 mos, the median PFS (mPFS) had not been reached (NR) (95% CI: 17.5, NA). Efficacy (CLL): The best response of 34 evaluable pts in Parts 1 and 2 included 91% ORR, 3% CR, 88% PR/PR-L, 9% SD, 0% PD. In Part 3, both arms achieved 100% ORR (all PRs). At a median follow-up of 20.2 mos, the mPFS was NR (95% CI: NA, NA), and the PFS estimate at 24 months was 95% for R/R, and 87% for TN, respectively, for evaluable CLL pts receiving Cirm/Ibr. Conclusions: Cirm/Ibr is a well-tolerated, active regimen in both MCL and CLL. For MCL, the mPFS of NR (95% CI: 17.5, NA) and CRR (41%), with all CRs remaining without PD, compare favorably to mPFS of 12.8 mos (95% CI 8.5-16.6) and CRR (20%) reported for single agent Ibr (Rule 2017). For CLL, the high ORR and PFS are encouraging, particularly for RR CLL. The study is ongoing, with MCL enrollment expanded to study Cirm + Ibr in pts who have had a suboptimal response to an Ibr regimen, or who have failed other approved BTKi agents. Clinical trial information: NCT03088878.

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