Safety and Efficacy of Subcutaneous (SC) Omacetaxine Mepesuccinate in Imatinib(IM)-Resistant Chronic Myeloid Leukemia (CML) Patients (pts) with the T315I Mutation – Results of An Ongoing Multicenter Phase II Study.

Abstract Background: Omacetaxine (homoharringtonine, HHT) shows clinical activity against Ph+ CML, with a mechanism of action independent of tyrosine kinase inhibition. Currently available tyrosine kinase inhibitors (TKIs) have not demonstrated activity in CML pts harboring the T315I BCR-ABL mutation. Study Goals: To evaluate the safety and efficacy of omacetaxine in pts with IM-resistant T315I+ Ph+ CML. Methods: Eligible pts include adult CML with confirmed T315I BCR-ABL mutation following imatinib failure after informed consent. Presence of T315I mutation is confirmed at one of 2 central reference labs. Induction schedule consists of 1.25 mg/m2 omacetaxine SC twice daily for 14 days every 28 days until complete hematologic response (CHR) or hematologic improvement (HI). Maintenance schedule may start after at least one induction cycle and after initial hematologic response. Maintenance treatment consists of 1.25 mg/m2 OMA SC twice daily for 7 days every 28 days, for up to 24 months. Study Results: To date, 50 pts have been enrolled, all having failed prior imatinib therapy, and 82% having failed 2 or more prior TKIs. Enrollment includes 26 pts in chronic phase (CP), 13 in accelerated phase (AP) and 11 in myeloid blast phase (BP). Median age: 58 yrs (19–84), 70% male. Mean baseline WBC values (/μl) were 11.51 (range 1.9–23.76) in CP, 18.88 (range 3.6– 78.2) in AP and 16.58 (range 2.4–51.5) in BP patients. Median disease duration is 58 months (range 5–285). Efficacy: Data are available for 30 pts: 15 CP, 10 AP and 6 BP pts. In CP pts, CHR has been achieved in 80% (12/15) with a median duration of response of 8 months (range 2.7 to 13.5+). Of these 12 pts achieving CHR, 11 pts continue on study with the remaining patient achieving complete cytogenetic response (CCyR) and being removed from treatment to receive allograft transplantation. The median time to hematologic response was 1.2 months (range 0.6 to 2.5). Overall cytogenetic response in CP pts is 20% (3/15) with 13% (2/15) achieving CCyR and 1 pt achieving a minimal cytogenetic reponse. Median duration of cytogenetic response is 9.1 months (range 7.1 to 9.2+) with one pt continuing in CCyR and the second patient receiving allograft as described above. In AP pts, overall hematologic response is 60% (6/10) with 5 of these patients remaining active in treatment. Two pts have achieved CHR, 3 returned to chronic phase and 1 showed HI. Median duration of response was 2.2 months (range 1 to 4.4+). Overall cytogenetic response rate in AP patients is 21% (3/14), with 2 pts achieving major cytogenetic response and 1 pt achieving minimal response. In BP patients, overall hematologic response rate is 33% (2/6) with 1 pt achieving CHR and 1 HI. Duration of response was 3.7 and 3.9 months respectively. The T315I mutated clone has been decreased below the limit of detection in 60% of evaluable patients. Safety: Data are available for 32 pts enrolled in all disease phases. The primary toxicity being myelosuppression which is reversible and managed by adjusting the number of dosing days received per cycle. Incidence of treatment emergent grade 3/4 events includes: thrombocytopenia 44%, neutropenia 34%, anemia 28%, febrile neutropenia 16%, and pancytopenia 9.4%. Injection site reactions have been mild with no grade 3–4 events reported. Four pts have died (3 BP, 1 AP) during the study period, all due to disease progression. Conclusions: Omacetaxine therapy in T315I mutated BCRABL+ IM-resistant CML is well tolerated and is producing durable CHRs and cytogenetic responses in these patients.

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Safety and Efficacy of Subcutaneous-Administered Omacetaxine Mepesuccinate in Imatinib-Resistant Chronic Myeloid Leukemia (CML) Patients Who Harbor the Bcr- Abl T315I Mutation–Results of An Ongoing Multicenter Phase 2/3 Study.

Blood ◽

10.1182/blood.v114.22.644.644 ◽

2009 ◽

Vol 114 (22) ◽

pp. 644-644 ◽

Cited By ~ 13

Author(s):

Jorge Cortes-Franco ◽

H. Jean Khoury ◽

Franck Emmanuel Nicolini ◽

Selim Corm ◽

Jeffrey H. Lipton ◽

...

Keyword(s):

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Median Overall Survival ◽

Cytogenetic Response ◽

Advisory Committees ◽

Safety And Efficacy ◽

Hematologic Response ◽

T315i Mutation ◽

Grade 3

Abstract Abstract 644 Background: Omacetaxine is a first-in-class cetaxine with clinical activity against Ph+ CML and a mechanism of action independent of tyrosine kinase inhibition. Currently available tyrosine kinase inhibitors (TKIs) have not demonstrated activity in CML patients (Pts) who harbor the Bcr-Abl T315I mutation. Study Goals: To evaluate the safety and efficacy of subcutaneously (SC) administered omacetaxine in Pts with imatinib (IM)-resistant T315I+ Ph+ CML. Methods: Eligible Pts include adult CML Pts in chronic, accelerated, or blast disease phase (CP, AP, BP) with a confirmed Bcr-Abl T315I mutation and resistance to IM therapy. Induction schedule: 1.25 mg/m2 SC omacetaxine twice daily for 14 days every 28 days until hematologic response. Maintenance dosing: 1.25 mg/m2 SC omacetaxine twice daily for 7 days every 28 days. Study Results: To date, 90 Pts have been enrolled, with data available for analysis on 66 Pts (40 CP, 16 AP and 10 BP). The median age was 58 yrs (19-83) with 70% male Pts and a median disease duration of 54 mo (5-285). All Pts failed prior IM therapy, and 79% failed two or more prior TKIs. The presence of baseline T315I mutation was confirmed in all Pts. Baseline clonal evolution was evident in 10 (25%) CP, 6 (38%) AP, and 7 (70%) BP Pts. Eight CP Pts entered the study in CHR. The median follow-up for all Pts was 6.4 mo (0.2 to 29.6). Efficacy: In CP Pts, CHR was achieved in 26 Pts and maintained in 8 Pts for an overall CHR rate of 85%; the median duration of CHR was 7.7+ mo (1.7 to 23.6). Overall cytogenetic response was 27.5% with 6 (15%) Pts achieving a major cytogenetic response (MCyR, 4 complete, 2 partial). The median duration of MCyR was 6+ mo (0.8 to 16.1). Major molecular response was achieved in 15% of Pts and a reduction of baseline T315I mutated clone occurred in 56.7% of CP Pts. In AP Pts, overall hematologic response was achieved in 6 (37.5%) Pts with 5 CHR and 1 return to chronic phase (RCP). Median duration of response was 3.9+ mo (1.7 to 14.8). One AP Pt achieved a complete cytogenetic response; duration 1.9+ mo. In BP Pts, overall hematologic response was achieved in 3 (30%) Pts with 2 CHR and 1 RCP. The median overall survival for CP Pts has not been reached and 35 (88%) Pts were alive at the time of data cut- off. The median overall survival was 18.8 mo for AP and 1.8 mo for BP Pts. Median time to progression was 11.2, 3.1, and 1.2 mo for CP, AP, and BP Pts, respectively. Safety: Grade 3/4 related events occurred in 45 of 66 (68%) Pts. The most commonly reported events were thrombocytopenia (58%), anemia (36%) and neutropenia (33%). Non-hematologic toxicities were primarily grade 1/2 with the most frequently reported events of diarrhea (44%), fatigue (35%), pyrexia (32%), nausea (26%), and asthenia (21%). Grade 3/4 non-hematologic toxicities were uncommon with no events occurring in >5% of Pts and infection (3%) the most common event. Treatment delays occurred in approximately 50% of the Pts with median duration of approximately 12 days for all disease phases and cycles (CP=12, AP=10, and BP=12 days). The primary causes of delay were thrombocytopenia, neutropenia and pancytopenia. Sixteen deaths occurred during the study (5 CP, 4 AP, and 7 BP).Three deaths (1 CP, 1 AP, and 1 BP) were considered to have a possible relationship to omacetaxine: sepsis, pancytopenia, and sudden death with unknown cause, respectively. Conclusions: Omacetaxine administered by subcutaneous injection produces durable hematologic and cytogenetic responses with a safety profile consisting mainly of hematologic toxicities. Omacetaxine may provide a treatment option for this patient population who currently has no available approved drug therapies. Disclosures: Cortes-Franco: ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Khoury:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nicolini:ChemGenex: Research Funding. Corm:ChemGenex: Research Funding. Lipton:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jones:ChemGenex: Research Funding. Hochhaus:ChemGenex: Research Funding. Craig:ChemGenex: Employment. Benichou:ChemGenex: Employment. Humphriss:ChemGenex: Employment. Kantarjian:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation

Blood ◽

10.1182/blood-2012-03-415307 ◽

2012 ◽

Vol 120 (13) ◽

pp. 2573-2580 ◽

Cited By ~ 84

Author(s):

Jorge Cortes ◽

Jeff H. Lipton ◽

Delphine Rea ◽

Raghunadharao Digumarti ◽

Charles Chuah ◽

...

Keyword(s):

Tyrosine Kinase ◽

Confidence Limit ◽

Chronic Phase ◽

Cytogenetic Response ◽

Phase 2 ◽

Lower Confidence Limit ◽

Hematologic Response ◽

Lower Confidence ◽

Omacetaxine Mepesuccinate ◽

T315i Mutation

Abstract Chronic myeloid leukemia (CML) patients with the BCR-ABL T315I mutation do not benefit from therapy with currently approved tyrosine kinase inhibitors. Omacetaxine mepesuccinate is a protein synthesis inhibitor that has demonstrated activity in cells harboring the T315I mutation. This phase 2 trial assessed the efficacy of omacetaxine in CML patients with T315I and tyrosine kinase inhibitor failure. Patients received subcutaneous omacetaxine 1.25 mg/m2 twice daily, days 1-14, every 28 days until hematologic response or a maximum of 6 cycles, and then days 1-7 every 28 days as maintenance. Results for patients treated in chronic phase are reported here. Patients (n = 62) received a median of 7 (range, 1-41) cycles. Complete hematologic response was achieved in 48 patients (77%; 95% lower confidence limit, 65%); median response duration was 9.1 months. Fourteen patients (23%; 95% lower confidence limit, 13%) achieved major cytogenetic response, including complete cytogenetic response in 10 (16%). Median progression free-survival was 7.7 months. Grade 3/4 hematologic toxicity included thrombocytopenia (76%), neutropenia (44%), and anemia (39%) and was typically manageable by dose reduction. Nonhematologic adverse events were mostly grade 1/2 and included infection (42%), diarrhea (40%), and nausea (34%). Omacetaxine may provide a safe and effective treatment for CML patients with T315I mutation. This study is registered at www.clinicaltrials.gov as NCT00375219.

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Nilotinib in chronic myeloid leukemia patients in accelerated phase (CML-AP) with imatinib (IM) resistance or intolerance: Longer follow-up results of a phase II study

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.7057 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 7057-7057

Author(s):

P. D. Le Coutre ◽

F. Giles ◽

A. Hochhaus ◽

J. F. Apperley ◽

G. Ossenkoppele ◽

...

Keyword(s):

Median Duration ◽

Elevated Serum ◽

Chronic Phase ◽

Dose Intensity ◽

Cytogenetic Response ◽

Serum Lipase ◽

Prior Therapy ◽

Hematologic Response ◽

Grade 3

7057 Background: Nilotinib is a potent and highly selective BCR-ABL inhibitor approved for the treatment of Ph+ CML patients (pts) in chronic phase or AP who are resistant or intolerant to prior therapy including IM. This study evaluated the efficacy and safety of nilotinib (400 mg bid) in CML-AP pts resistant or intolerant to IM. Methods: Primary endpoint was confirmed hematologic response (HR). Secondary endpoints included major cytogenetic response (MCyR), time to progression, overall survival (OS), and safety. Results: 137 CML-AP pts (80% IM-resistant; 20% IM-intolerant with resistance) with minimum follow-up of 11 months (mos) (median age, 57 years; median duration of prior IM treatment, 28 mos) were included. IM-intolerant pts were also IM-resistant and without MCyR at study entry. 79% pts had prior IM ≥600 mg/day. Median dose intensity of nilotinib was 775 mg/day and median duration of exposure was 272 days. 56% had confirmed HR and 31% had complete hematologic response (CHR). 30% of IM-resistant and 37% of IM-intolerant pts achieved CHR. Responses were rapid, with a median time to first HR of 1 mo. HRs were durable at 24 mos with 54% of pts maintaining their response. MCyR was achieved in 32% of pts (30% in IM-resistant, 41% in IM-intolerant) and complete cytogenetic response in 20% of pts (18% in IM-resistant, 30% in IM-intolerant). Cytogenetic responses were also durable with 70% of pts maintaining MCyR at 24 mos; 83% of pts maintained CCyR at 12 mos. Estimated OS at 24 mos was 67%. Only 9% of pts discontinued therapy due to drug-related adverse events (AE). The most frequently reported grade 3/4 laboratory abnormalities were thrombocytopenia (41%), neutropenia (42%), anemia (25%), elevated serum lipase (18%), and hypophosphatemia (14%). The rates of grade 3/4 myelosuppression were low, predictable, and easily managed with median onset of 14 to 29 days and median duration of 8 to 26 days. Grade 3/4 non-hematologic AEs were rare (< 1%) and included nausea, fatigue, and diarrhea. Conclusions: These long-term follow-up results confirm that nilotinib induces rapid and durable responses in CML-AP pts who failed prior IM due to intolerance or resistance, with a favorable risk/benefit. [Table: see text]

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Safety and Efficacy of Subcutaneous-Administered Omacetaxine Mepesuccinate in Chronic Myeloid Leukemia (CML) Patients Who Are Resistant or Intolerant to Two or More Tyrosine Kinase Inhibitors – Results of A Multicenter Phase 2/3 Study.

Blood ◽

10.1182/blood.v114.22.861.861 ◽

2009 ◽

Vol 114 (22) ◽

pp. 861-861 ◽

Cited By ~ 10

Author(s):

Jorge Cortes-Franco ◽

Digumarti Raghunadharao ◽

Purvish Parikh ◽

Meir Wetzler ◽

Jeffrey H. Lipton ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Median Overall Survival ◽

Cytogenetic Response ◽

Advisory Committees ◽

Safety And Efficacy ◽

Hematologic Response ◽

Grade 3

Abstract Abstract 861 Background: Omacetaxine is a first-in-class cetaxine with clinical activity against Ph+ CML and a mechanism of action independent of tyrosine kinase inhibition. The development of TKI resistance and intolerance is an emerging problem and patients (Pts) who have failed multiple TKIs may benefit from an alternative therapy for CML. Study Goals: To evaluate the safety and efficacy of SC omacetaxine in CML Pts who are resistant and/or intolerant to two or more TKIs. Methods: Eligible Pts included adult CML Pts in chronic, accelerated, or blast disease phase (CP, AP, BP) with resistance and/or intolerance to at least two TKIs. Bcr-Abl mutational analysis was performed at one of 2 central reference laboratories and Pts harboring the T315I Bcr-Abl mutation were enrolled in a separate clinical trial. Induction schedule: 1.25 mg/m2 SC omacetaxine twice daily for 14 days every 28 days until hematologic response. Maintenance dosing: 1.25 mg/m2 SC omacetaxine twice daily for 7 days every 28 days. Study Results: To date, 99 Pts have enrolled, with data available for analysis on 65 Pts (30 CP, 20 AP and 15 BP). The median age was 57 yrs (23-78) with 52% male and a median disease duration of 77 mo (1-197). Nearly all (64/65, 99%) Pts failed prior IM therapy and 57% failed 3 or more prior TKIs. Baseline mutations were identified in 21 (32%) Pts with 10 non-P Loop, 7 P Loop and 4 compound mutations. Baseline clonal evolution was evident in 5 (17%) CP, 8 (40%) AP, and 13 (87%) BP Pts. Six CP Pts entered the study in CHR. The median follow-up for all Pts is 4.0 mo (0.3 to 14.7). Efficacy: In CP Pts, CHR was achieved in 18 Pts and maintained for more than 8 weeks in the 6 Pts enrolled with baseline CHR, for an overall CHR rate of 80%; median duration 4.7+ mo (1.4 to 13). Major cytogenetic response (MCyR) was achieved in 6 (20%) CP Pts (1 complete, 5 partial); median duration 1.6+ mo (0.0 to 2.9). Major molecular response was achieved in 10% of CP Pts. In AP Pts, overall hematologic response was achieved in 15 (75%) Pts; 12 CHR and 3 return to chronic phase (RCP); median duration 2.5+ mo (1.8 to 10.5). One (5%) AP Pt achieved a complete CyR, identified immediately prior to data cut-off and ongoing. In BP Pts, overall hematologic response was achieved in 8 (53.3%); 6 CHR and 2 RCP. Three Pts (2 CP, 1 AP) received bone marrow/stem cell transplants after achieving major cytogenetic response, a therapeutic option not available to them at study enrollment. No deaths occurred in CP Pts. The median overall survival for AP Pts has not been reached and 13 Pts were alive at the time of data cut-off. Median overall survival was 14.5 mo for BP Pts. Median time to progression was 11.1, 5.7, and 2.6 mo for CP, AP, and BP Pts, respectively. Safety: Grade 3/4 related events occurred in 47/65 (72%) of Pts. The most commonly reported events (>15%) were thrombocytopenia (43%), neutropenia (29%), and anemia (22%). Non-hematologic toxicities were generally grade 1/2 with the most frequently reported; diarrhea (32%), nausea (26%), pyrexia (23%), headache (20%), fatigue (19%), vomiting (17%), and asthenia (17%). Grade 3/4 non-hematologic toxicities were uncommon with no events occurring in >5% of Pts and fatigue (3%) the most common event. Treatment delays occurred in approximately 50% of the Pts with median duration of approximately 9 days for all disease phases and cycles (CP=7, AP=11, and BP=12 days). The primary causes of delay were thrombocytopenia, neutropenia and pancytopenia. Deaths occurred in 6 (9.2%) Pts, including 2 (10%) AP pts and 4 (26.7%) BP Pts. Of the deaths, one occurrence in an AP Pt was considered to be possibly related to omacetaxine treatment (febrile neutropenia). Conclusions: Omacetaxine administered by SC injection produced hematologic and cytogenetic responses with a safety profile primarily consisting of hematologic toxicities. This study demonstrated that omacetaxine may be a potential treatment option for CML Pts who have failed multiple TKIs. Disclosures: Cortes-Franco: ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Raghunadharao:ChemGenex: Research Funding. Parikh:ChemGenex: Research Funding. Wetzler:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lipton:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jones:ChemGenex: Research Funding. Hochhaus:ChemGenex: Research Funding. Kantarjian:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Craig:ChemGenex: Employment. Benichou:ChemGenex: Employment. Humphriss:ChemGenex: Employment. Nicolini:ChemGenex: Research Funding.

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Dasatinib (SPRYCEL®) in Patients (pts) with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Who Are Imatinib-Resistant (im-r) or -Intolerant (im-i): Updated Results from the CA180-015 ‘START-L’ Study.

Blood ◽

10.1182/blood.v108.11.286.286 ◽

2006 ◽

Vol 108 (11) ◽

pp. 286-286 ◽

Cited By ~ 4

Author(s):

Herve Dombret ◽

O.G. Ottmann ◽

G. Rosti ◽

B. Simonsson ◽

R.A. Larson ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Median Duration ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Cytogenetic Response ◽

Molecular Response ◽

Cell Transplant ◽

Hematologic Response ◽

Grade 3 ◽

Philadelphia Chromosome Positive

Abstract Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC. Relapsing pts with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) who have been previously treated with chemotherapy including im have a very poor prognosis. START-L is an open label, multi-center, global phase-II study, which treated 46 im-r or im-i pts with Ph(+) ALL from January through June 2005. Dasatinib was given orally, 70 mg twice daily (BID) with escalation to 100 mg BID for poor response or reductions to 50 mg and 40 mg BID for toxicity. Response was assessed on weekly blood counts and monthly bone marrow exams, including cytogenetics. Mutation analysis was conducted at baseline and at end of study. Quantitative PCR was carried out pretreatment and at the time of complete cytogenetic response (CCyR). At the time of this update, all 46 pts had a minimum of 9 months (mo) of follow-up. Of these, 44 (96%) were im-r; due to the small number of im-i pts, data for all pts are presented. 59% of patients were male and median age was 48 years. The median time from initial Ph(+) ALL diagnosis to first dose was 18 mo. All patients had been pretreated with im including 46% with 600 mg per day or more, and 52% whose duration of im treatment was more than 12 mo. 37% of the pts had received a stem cell transplant. At baseline, 67% of pts had WBC <2000/mm3, 74% had platelets <100 × 103/mm3, and 24% had extramedullary disease outside of the spleen. In the 40 pts with baseline mutation data, im-resistant BCR-ABL mutations were observed in 78%, one with T315I. The median duration of therapy was 3.0 mo (range 0.03–16.5) for all pts and was 13.0 mo (9.2–16.5) for pts still on study. The overall complete hematologic response rate was 35%. The major cytogenetic response was 57%, including 54% CCyR. The major hematologic response (MHR) in the 31 pts with baseline mutations was 45%. The median duration of MHR was 11 mo and the median progression-free survival was 3.7 mo (95% CI 1.6–6.1). Grades 3 and 4 thrombocytopenia occurred in 13% and 67%, respectively and grades 3 and 4 neutropenia occurred in 27% and 52% of pts, respectively. Most frequent non-hematologic toxicities included diarrhea in 30% (grade 3–4, 7%), nausea in 22% (no grade 3–4), pyrexia in 22% (grade 3–4, 2%), and pleural effusion in 22% (grade 3–4, 7%) of pts. Dose was reduced in 30% and interrupted in 43% of pts, primarily due to non-hematologic toxicities. Dasatinib has important efficacy in this Ph(+) ALL pt population. Updated efficacy (including molecular response), safety, and mutational analysis data will be presented at the meeting.

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A Phase 1 Study of DCC-2036, a Novel Oral Inhibitor of BCR-ABL Kinase, in Patients with Philadelphia Chromosome Positive (Ph+) Leukemias Including Patients with T315I Mutation

Blood ◽

10.1182/blood.v118.21.601.601 ◽

2011 ◽

Vol 118 (21) ◽

pp. 601-601 ◽

Cited By ~ 5

Author(s):

Jorge E. Cortes ◽

Moshe Talpaz ◽

Hagop M Kantarjian ◽

Hedy Smith ◽

Dale Bixby ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Dose Level ◽

Research Funding ◽

Kinase Inhibitor ◽

Cytogenetic Response ◽

Lower Extremity Weakness ◽

Hematologic Response ◽

T315i Mutation ◽

Dose Levels

Abstract Abstract 601 Background. DCC-2036 is a novel and potent tyrosine kinase inhibitor (TKI) which binds to a novel region called the switch pocket, thereby preventing BCR-ABL from adopting a conformationally active state. Efficacy against multiple imatinib-resistant BCR-ABL mutants has been demonstrated both in vitro and in vivo (Chan et al., Cancer Cell 2011;19:556). Importantly, DCC-2036 retains full potency against the T315I mutant in preclinical efficacy studies. Methods. This study was designed to find the maximal tolerated dose (MTD) of DCC-2036 when administered daily as a single-agent on a 28-day cycle. Eligible patients included adults with Ph+ CML/ALL who were refractory/intolerant to ≥2 TKI's or were T315I positive. Initially DCC-2036 capsules were administered orally once daily (QD) at increasing dose levels. Only 1 patient was enrolled in each of the lowest dose cohorts of 57mg QD and 114 mg QD. For higher doses, 3– 6 patients were enrolled into each ascending dose cohort with standard dose limiting toxicity (DLT) rules evaluating safety in cycle 1 to determine dose escalation. A transition from unformulated capsules (C) to formulated tablets (T) occurred after the 1200 mg QD dose level. Paired blood samples were obtained for PK and PD assessments. Results. 30 patients (16 males, 14 females; median age 59, range 31 – 80) with CML including 19 in Chronic (CP); 8 in Accelerated (AP) and 3 in Blast (BP) Phase were enrolled. Enrolled patients had received 1–6 prior CML treatments, and 11 patients had the T315I mutation. To date, a total of 212.5 (median 5.6; range 0.2 – 23.4) 28-day cycles were administered over 10 dose levels either as C (7 dose levels) or T (3 dose levels). The 7 C dose levels were studied first and included 57 mg QD through 1200 mg QD. Following transition to T, evaluation continued with 100 mg QD, 100 mg twice daily (BID), and 200 mg BID. Two reversible DLTs (Grade 3 peripheral neuropathy and Grade 4 lower extremity weakness) occurred during the initial treatment cycle at the 200 mg T BID dose level. Evaluation of 6 patients at the 150 mg T BID dose level determined that dose to be the MTD. Preliminary safety data show that other Grade (Gr) 3/4 adverse events (AEs) were Gr 3 slurred speech and Gr 3 eruptive nevi. Gr 1/2 AEs included dry mouth, constipation, diarrhea, paresthesias, and retinal vein occlusion. There was 1 case of Gr 2 pancreatitis that recurred on rechallenge in a patient with previous pancreatitis with nilotinib. Preliminary responses include one major molecular response in a CP patient with T315I mutation who started on capsules and transitioned to 100 mg T QD. There was one complete cytogenetic response in a CP patient at 100 mg T BID, and one partial cytogenetic response in a CP patient who started on capsules and transitioned to 100 mg T BID. One patient with AP CML and T315I mutation had a complete hematologic response at 450 mg C QD. Another patient with AP CML had a partial hematologic response after receiving 200 mg BID for 1 cycle and then downdosing to 100 mg T BID. Four out of 8 patients receiving 100 mg tablets and evaluable for efficacy (completed 3 cycles of treatment) had responses. PK results indicate dose-related, nonlinear increases in both peak plasma concentration (Cmax) and exposure (AUC). PD results reveal both acute and steady state post-treatment reductions in phospho-protein levels on Days 1 and 8. Marked reductions in pSTAT5 and pCRKL have been observed in subjects with both CP and AP and appear to be required for clinical response. Conclusion. The MTD of DCC-2036 tablets is 150 mg BID. Preliminary results suggest that DCC-2036 is well tolerated and has anti-leukemia activity in subjects with refractory CML and T315I positive disease. PD results are consistent with inhibition of BCR-ABL signaling in this first-in-man study of a switch pocket tyrosine kinase inhibitor. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Chemgenex: Consultancy, Research Funding; Deciphera Pharmaceuticals: Research Funding. Bixby:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. Rafferty:Deciphera Pharmaceuticals: Employment. Berger:Deciphera Pharmaceuticals: Employment. Wise:Deciphera Pharmaceuticals LLC: Employment. Rutkoski:Deciphera Pharmaceuticals: Employment. Smith:Deciphera Pharmaceuticals: Employment. Van Etten:Deciphera Pharmaceuticals: Consultancy, Research Funding.

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Safety and efficacy of a novel anti-CD20/CD19 bi-specific CAR T-cell therapy (C-CAR039) in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2507 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2507-2507

Author(s):

Aibin Liang ◽

Lili Zhou ◽

Ping Li ◽

Wenjuan Yu ◽

Min Yang ◽

...

Keyword(s):

Clinical Trial ◽

Median Time ◽

Median Duration ◽

Conditioning Regimen ◽

Early Clinical Trial ◽

Safety And Efficacy ◽

Car T ◽

Duration Of Response ◽

Grade 3

2507 Background: C-CAR039 has been developed as a novel 2nd generation 4-1BB bi-specific CAR-T targeting both CD19 and CD20 antigens with an optimized bi-specific antigen binding domain. C-CAR039 can eradicate CD19/CD20 single or double positive tumor cells in vitro and in vivo. The tissue cross reactivity and whole genome membrane proteome array studies further confirmed the specificity of C-CAR039. Methods: GMP manufacturing of C-CAR039 was carried out in a serum free and fully closed semi-automatic system. Dose escalation and expansion studies were conducted to evaluate the safety and efficacy of C-CAR039 in r/r B-NHL patients. C-CAR039 was administered as a single intravenous dose after a 3-day cyclophosphamide plus fludarabine conditioning regimen. Results: As of 1/31/2021, 28 patients were infused and 25 (DLBCL, n = 22; PMBCL, n = 1; tFL, n = 1; FL, n = 1) were evaluable for safety and efficacy at dose ranges of 1.0 x 106 to 5.0x106 CAR-T cells/kg. The median age was 54 (range, 28-71) years, median number of prior lines of therapy was 3 (range, 1–5), 76% (19/25) of patients were in Ann Arbor Stage III/IV, and 80% (20/25) were refractory to their last treatment. 5 patients (20%) received bridging therapy. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT 2019 criteria. Of the 25 patients, 24 (96%) experienced CRS, 23 (92%) were grade 1 or 2, 1 patient was grade 3. Median time to onset of CRS was 3 days (range, 0-10), with median duration of 4 days (range, 1-25). 2 patients had a grade 1 ICANS. Grade≥3 neutropenia, anemia, thrombocytopenia and infection were reported in 88%, 40%, 16% and 0% of patients, respectively. The best overall response rate was 92%, complete response (CR) rate was 84% and median time to response was 1.0 month (range, 0.9-1.2). With a median follow-up of 5.3 months, 76% remained in CR. Kaplan Meyer estimation of PFS at 6 months was 87.3% (95% CI, 71.2 to 100.0). Median duration of response has not been reached. Furthermore, C-CAR039 showed an encouraging cellular kinetic profile. In 25 evaluable patients, the median Tmax was 11 day, the median Cmax was 139,497 copies/mg gDNA, and the median AUC0̃28DAY of 1,673,844 day*copies/μg gDNA. Conclusions: C-CAR039 demonstrated a favorable safety profile and promising efficacy in this early clinical trial in patients with r/r B-NHL that might allow it to differentiate from existing therapies. The early clinical efficacy signal is encouraging and compares favorably to anti-CD19 CAR-T and peer therapies. These findings will be evaluated in more patients with longer follow-up to confirm safety, efficacy and duration of response. Clinical trial information: NCT04317885 , NCT04655677 , NCT04696432 , NCT04693676 .

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Dasatinib in Patients with Imatinib-Resistant Chronic Myeloid Leukemia: Experience from a Cancer Centre in Northern India

Blood ◽

10.1182/blood.v112.11.4290.4290 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4290-4290

Author(s):

Vineet Talwar ◽

Dinesh Bhurani ◽

Dinesh Chandra Doval ◽

Ajay Kumar Sharma

Keyword(s):

Adverse Events ◽

Median Duration ◽

Blast Crisis ◽

Chronic Phase ◽

Cytogenetic Response ◽

Imatinib Therapy ◽

Toxicity Profile ◽

Imatinib Resistance ◽

Hematologic Response ◽

Favorable Toxicity Profile

Abstract INTRODUCTION: Dasatinib is a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases. It is structurally unrelated to imatinib, binding to the oncologically relevant catalytically active conformation of BCR ABL. It is active against all tested BCR ABL mutations except T315I that confer Imatinib resistance. AIM: Primary Aim: Survival with Dasatinib. Secondary Aim: Toxicity profile of Dasatinib. MATERIALS AND METHODS: A total number of 12 patients were included in this study with a median age of 40 years. Five patients were male and seven female. The median duration, since starting therapy for CML was 58.9 months. The median duration since start of treatment with dasatinib was 9.5 months. Out of the 12 patients, 9 were in chronic phase (75%) and 3 were in myeloid blast crisis (25%). Amongst these, 8 patients (66.7%) had taken prior imatinib therapy for more than 3 years. The dose of prior imatinib therapy ranged from 400 mg in patients of chronic phase to upto 800mg in blast crisis patients. For inclusion in the study, patients were required to have adequate hepatic and renal function and eastern co-operative oncology group (ECOG) performance score of 2 or lower. Exclusion criteria included previous dasatinib therapy, significant cardiovascular disease or significant bleeding disorder unrelated to CML. Imatinib failure was defined as progression from chronic phase to blast crisis while receiving 400mg/day or more imatinib or from accelerated phase to blast crisis while receiving 600mg/day or more imatinib. The hematology and cytogenetic responses were accessed as per standard criteria. RESULTS: A total number of 12 patients were enrolled in this pilot study out of which 7 are still on therapy. 5 patients discontinued therapy due to death. The median duration of dasatinib therapy was 7.5 months. The longest follow up patient on therapy being 20 months. The median daily dasatinib dose was 100mg. Nine patients (75%) had a major hematologic response and three patients (25%) had minor hematologic response. Dasatinib induced a major cytogenetic response in 5 (41.7%) patients, minor cytogenetic response in 1 (8.5%) patients, and minimal cytogenetic response in 4 (33.3%) patients. No cytogenetic response was seen in 2 patients of blast crisis. The median duration of survival was not achieved till August 2008. The one year survival by Kaplan-Meier method is 64% (1 month – 19 months). Dasatinib had a favorable toxicity profile. Among the non hematologic events, the most frequent adverse events were diarrhea (3/12), vomiting (3/12), peripheral edema (4/12), arthralgia (3/12), fatigue (5/12), rash (3/12), epistaxis (2/12), fever (1/12) and headache (2/12). Dose interruption was required for one patient with pleural effusion which was reversible with diuretics and steroids. No patients had grade 4 toxicity. The cytopenias were generally reversible and could be managed effectively by dose interruption or reduction. Since these patients had prior therapy with imatinib, assessment of relative contribution of therapy to myelosuppression could be a confounding factor. CONCLUSION: Dasatinib induced hematologic and cytogenetic response in majority of patients who had progressed on imatinib therapy. Dasatinib has a favorable toxicity profile. The hematologic and non hematologic adverse events could be managed with dose alterations. It presents a potentially new therapeutic option for patients with imatinib failure or intolerance.

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Subcutaneous Omacetaxine (OM) Treatment of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients Following Multiple Tyrosine Kinase Inhibitor (TKI) Failure

Blood ◽

10.1182/blood.v116.21.2290.2290 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2290-2290 ◽

Cited By ~ 2

Author(s):

Jorge E. Cortes ◽

Meir Wetzler ◽

Jeff Lipton ◽

Franck E Nicolini ◽

Michele Baccarani ◽

...

Keyword(s):

Bone Marrow ◽

Adverse Events ◽

Median Duration ◽

Bone Marrow Failure ◽

Single Agent ◽

Chronic Phase ◽

Cytogenetic Response ◽

Employment Equity ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 2290 Introduction: Multiple TKI failure is a growing problem in a subset of CML patients. Treatment with a third TKI after two have failed often yields poor results. New treatment options are needed for this patient population. OM is a first-in-class cetaxine with demonstrated activity as a single agent in CML. It inhibits the production of short-lived oncoproteins (such as Mcl-1) involved in cancer cell survival via a mechanism independent of Bcr-Abl binding. Several studies have suggested that OM has a favorable toxicity profile when given to patients with CML via the subcutaneous route. We explored OM efficacy and safety in a subset of patients who had received therapy with multiple prior approved TKI. Methods: We analyzed a subset of adult CML-CP patients who had received two or more TKI (imatinib, dasatinib, nilotinib), from a combined interim dataset of two prospective Phase 2 studies (CML-202, for patients with the T315I kinase domain mutation, and CML-203, for patients with failure to ≥2 TKI) utilizing OM in the treatment adult patients with all phases of CML who had failed TKI. TKI failure was defined as no complete hematologic response (CHR) by 12 weeks (wk), no cytogenetic response by 6 months (mo), no major cytogenetic response (MCyR) by 12 mo, loss of CHR or MCyR, or progressive leukocytosis. The focus of this analysis was to assess the CHR and MCyR response rates as well as the overall safety of OM in these patients. Adverse events presented are Grade 3/4 events that occurred in ≥ 5% of patients (regardless of causality). Results: A total of 73 of the 93 CML-CP patients from these two studies had received two or more TKI prior to OM treatment. Median time from initial CML diagnosis to first dose of OM was 74.4 months. Mutations of any kind were seen in 48% of the patients, whereas 29% had no identified mutation and 23% had no available data on mutation status. Sixty (82%) of these 73 patients achieved or maintained (twelve patients were in CHR at study entry) a CHR and 17 (23%) achieved a MCyR (9 complete and 8 partial). The median duration of MCyR was 4.4+ months (range 1.2–14.1+). Median overall survival for patients treated with OM after failure of 2 or more TKI has not yet been reached [95% Confidence Interval (CI) 22.9, NA months] (Figure 1). Eleven patients had a treatment—emergent adverse event leading to death, and two deaths were probably related to study drug. Median progression-free survival was 11.1 months (95% CI 6.5, 13.8 months). Median follow-up time was 7.5 months for all patients with twenty-five patients remaining on study at the time of this data cut. A total of 36 of the 93 CP patients from these two studies had been treated with three or more TKI; 27 (75.0%) achieved or maintained a CHR and 7 (19.4%) achieved a MCyR (4 complete and 3 partial) on OM treatment. The median duration of MCyR in this group was 4.0+ months (range 1.2–11.5+) at the time of data cut-off. The primary Grade 3/4 adverse events in patients who received OM after failure of 2 or more TKI were hematologic, including thrombocytopenia (64%), neutropenia (48%) and anemia (40%) most commonly, followed by febrile neutropenia (12%), bone marrow failure (12%), pancytopenia (7%) and febrile bone marrow aplasia (6%). These events were dosing schedule dependent. Clinical sequelae were uncommon and managed with transient treatment interruptions and dose adjustments. Grade 3/4 non-hematologic adverse events were infrequent, with only fatigue (6%) occurring ≥5% of patients. Conclusions: OM, through a mechanism of action independent of Bcr-Abl, may offer a clinically viable option for patients who have progressed on multiple TKI treatment. Disclosures: Off Label Use: The drug is currently in development and has an NDA submitted for use in TKI resistant CML. Cram: ChemGenex: Employment, Equity Ownership. Humphriss: ChemGenex: Employment, Equity Ownership. Benichou: ChemGenex: Consultancy, Equity Ownership. Craig: ChemGenex: Employment, Equity Ownership, Executive Management Level.

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Differences in Haematological and Non Haematological Toxicity during Treatment with Imatinib in Early and Late Chronic Phase Chronic Myeloid Leukemia Patients

Blood ◽

10.1182/blood.v112.11.4281.4281 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4281-4281

Author(s):

Massimo Breccia ◽

Roberto Latagliata ◽

Laura Cannella ◽

Ida Carmosino ◽

Caterina Stefanizzi ◽

...

Keyword(s):

Weight Gain ◽

Side Effects ◽

Adverse Events ◽

Median Duration ◽

Chronic Phase ◽

Cytogenetic Response ◽

Hematological Toxicity ◽

Severe Thrombocytopenia ◽

Muscle Cramps ◽

Grade 3

Abstract Imatinib is a relatively specific inhibitor of the BCR/ABL tyrosine kinase, effective in chronic myeloid leukaemia (CML). Aim of present study was to analyse the frequency and type of hematological and non hematological adverse events in our series of late and early chronic phase CML patients treated with imatinib and correlate the grade of hematological toxicity with the response obtained. Hematological adverse events were seen in 59 out of 150 (39%) late CP patients: 20 patients (34%) experienced toxicity grade 1, 25 (42%) had toxicity grade 2 and 14 (24%) had toxicity grade 3–4. Of 100 early CP patients, 26 (26%) experienced hematological adverse event: 42% had toxicity grade 1, 50% had toxicity grade 2 and 7% had toxicity grade 3–4. Statistical differences were detected between early and late CP patients for grade 1–2 and 3–4 toxicity. Median duration of toxicity in late CP patients was 20 days (range 4–41) for grade 1, 16 days (range 4–27) for grade 2 and 18 days (range 8–40) for grade 3–4. In early CP patients the median duration of toxicity was 10 days (range 4–21) for grade 1, 14 days (range 6–28) for grade 2 and of 10 days (range 7–15) for grade 3–4. We analysed the clinical features associated to a greater risk of myelosuppression and found that a lower haemoglobin level was significant in early CP patients while a history of cytopenia during IFN therapy and a longer time elapsing from diagnosis was significant in late CP patients. The occurrence of hematological toxicity in late CP patients was associated to the persistent lack of complete cytogenetic response, whereas this correlation was not apparent in early CP patients. We compared the incidence of non hematological adverse events occurring in late and in early CP patients and found that in these latter some side effects were more frequent, such as weight gain, periorbital oedema (p=0.02), muscle cramps (p=0.03), skin rashes (p=0.002), diarrhoea (p=0.01), weeping (p=0.001) and infections (p=0.001). In late CP patients compared to early CP patients, we found as significant the occurrence during therapy of bone pain (p=0.001) and of hemorrhagic symptoms (p=0.002) in the absence of severe thrombocytopenia. Grade 3–4 adverse events were recorded at rates below 4% and decreased over time: in late CP patients hemorrhages and muscle cramps were the most common side effects of grade 3–4, whereas in early CP patients the most frequent events were nausea, weight gain and cutaneous rash. Cardiac toxicity was observed in 3 out of 250 patients and cardiac events most frequently occurred in elderly patients with pre-existing conditions that predispose to fluid retention, with overall frequency of these events being 1%. In conclusion, we have observed that hematological and non-hematological side effects during imatinib therapy are different among late and early CP patients and that severe hematological toxicity may influence cytogenetic response.

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