Nilotinib in Chronic Myeloid Leukemia Patients in Chronic Phase (CMLCP) with Imatinib Resistance or Intolerance: 2-Year Follow-up Results of a Phase 2 Study.

Abstract Background: Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia patients in chronic (CML-CP) or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. Methods: This open-label, single-arm, phase 2 study was designed to evaluate the efficacy and safety of nilotinib in CML-CP patients resistant or intolerant to imatinib. Imatinib intolerant patients with prior major cytogenetic response (MCyR) on imatinib were not eligible for this trial. Nilotinib was dosed at 400 mg twice daily with the option of dose escalation to 600 mg twice daily if responses were inadequate. Rate of MCyR was the primary endpoint. Secondary endpoints included complete cytogenetic response (CCyR), complete hematological response (CHR), duration of MCyR, survival, and safety. Results: A total of 321 CML-CP patients (71% imatinib-resistant; 29% imatinib-intolerant) were evaluated. Most patients were heavily pretreated with 72% having received more than 600 mg/day of imatinib prior to study entry. Furthermore, imatinib-intolerant patients could not have achieved prior MCyR on imatinib therapy. Median duration of prior imatinib treatment was 33 months (range 0.3–95 months). Dose reductions (25%) and discontinuations (15%) due to adverse events were infrequent on nilotinib therapy and median dose intensity (788 mg/day; range 151–1112 mg/day) closely approximated the planned dose. Median duration of exposure was 465 days (15.5 months). Overall, nilotinib therapy resulted in rapid and durable hematologic and cytogenetic responses. Of all imatinib-resistant and –intolerant patients, 58% achieved MCyR (1 month median time to MCyR), with 72% of patients having a baseline CHR achieving MCyR. The MCyR rate was 63% in imatinibintolerant and 56% in imatinib-resistant patients, respectively. Overall, 42% of patients achieved a CCyR (50% in imatinib-intolerant and 39% in imatinib-resistant patients, respectively). Responses were durable, with 84% of patients maintaining their MCyR at 18 months. Estimated overall survival (OS) rates at 12 and 18 months were 95% and 91%, respectively. Nearly half of all patients (47%) were still receiving nilotinib at the time of cut-off for data analysis. Longer follow-up has not significantly changed the safety profile of nilotinib. The most frequently reported grade 3/4 biochemical laboratory abnormalities were elevated lipase (16%), hypophosphatemia (15%), hyperglycemia (12%), and elevated total bilirubin (7%). Overall, biochemical laboratory abnormalities were transient and clinically asymptomatic. Grade 3/4 non-hematologic adverse events were infrequent with rash, headache, and diarrhea occurring in only 2% of patients. No pleural or pericardial effusions were documented during nilotinib therapy. The most common grade 3/4 hematological laboratory abnormalities included neutropenia (30%), thrombocytopenia (28%), and anemia (10%). Overall, QTcF changes greater than 60 milliseconds from baseline were infrequent, occurring in only 8 patients (2.5%), and QTcF prolongation >500 milliseconds was uncommon (<1%), occurring in only 3 patients. Brief dose interruptions were sufficient to manage most adverse events. Conclusions: Nilotinib is highly effective and produces rapid and durable responses in CML-CP patients who failed prior therapy including imatinib due to resistance or intolerance and is an important treatment option for this patient population. Nilotinib is well tolerated with minimal occurrence of grade 3/4 adverse events; safety profile has not changed with longer follow-up.

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Nilotinib in Chronic Myeloid Leukemia Patients in Accelerated Phase (CML-AP) with Imatinib Resistance or Intolerance: 2-Year Follow-up Results of a Phase 2 Study

Blood ◽

10.1182/blood.v112.11.3229.3229 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3229-3229 ◽

Cited By ~ 11

Author(s):

Philipp D. le Coutre ◽

Francis Giles ◽

Andreas Hochhaus ◽

Jane F. Apperley ◽

Gert Ossenkoppele ◽

...

Keyword(s):

Overall Survival ◽

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Myeloid Leukemia ◽

Cytogenetic Response ◽

Phase 2 ◽

Time To Progression ◽

Phase 2 Study ◽

Grade 3

Abstract Background: Nilotinib is a rationally designed, potent and highly selective BCR-ABL kinase inhibitor, and binds to ABL with higher affinity and improved topological fit compared to imatinib. Nilotinib is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myeloid leukemia pts in chronic (CML-CP) or accelerated phase (CML-AP) resistant or intolerant to prior therapy including imatinib. Methods: This open-label, single-arm, phase 2 study was designed to evaluate the efficacy and safety of nilotinib in CML-AP pts who are resistant or intolerant to imatinib. Nilotinib was dosed at 400 mg twice daily with the option to dose escalate to 600 mg twice daily for lack of response. The primary endpoint was confirmed hematologic response (HR). Complete hematologic response (CHR) was defined as meeting all of the following criteria: myeloblast count <5% in bone marrow, no myeloblast in peripheral blood, neutrophil count ≥1.5 × 109/L, platelet count ≥100×109/L, basophils <5%, no evidence of extramedullary involvement. Secondary endpoints included major cytogenetic response (MCyR), time to progression, overall survival, and safety. Results: A total of 138 CML-AP pts (80% imatinib resistant; 20% imatinib intolerant) who received at least 1 dose of nilotinib were included in the analysis. Median age was 57 years (range, 22–82 years); median duration of prior imatinib treatment was 28 months. Seventy-nine percent of pts received prior imatinib doses ≥600 mg/day; overall, 45% received ≥800 mg/day imatinib. Median dose intensity of nilotinib was near planned dose at 775 mg/day with a median duration of exposure of 253 days (8.4 months). Of 134 pts with at least 6 months of follow-up included in the efficacy analysis, 56% had confirmed HR and 30% had CHR. Responses were rapid, with a median time to first HR of 1 month. Hematologic responses were durable at 1 year, with 78% of pts who achieved HR maintaining their response. MCyR and complete cytogenetic response (CCyR) occurred in 32% and 19% of pts, respectively. Cytogenetic responses were also durable, with 69% of pts maintaining MCyR at 18 months. Median time to progression was 16 months in this population of pts with advanced disease. Progression was defined as any of the following: investigator’s evaluation as progression, development of CML-AP or blast crisis, loss of CHR, loss of MCyR. Estimated overall survival at 1 year is 82%. Longer follow-up has not significantly changed the safety profile of nilotinib. The most frequently reported grade 3/4 laboratory abnormalities were thrombocytopenia (40%), neutropenia (40%), anemia (25%), elevated serum lipase (17%), and hypophosphatemia (12%). Grade 3/4 non-hematologic adverse events were uncommon (<1%) and included rash, nausea, fatigue, and diarrhea. Brief dose interruptions were sufficient to manage most adverse events. Conclusions: The long-term follow-up results of this phase 2 study confirm that nilotinib induces rapid and durable responses in pts with CML-AP who failed prior imatinib therapy due to intolerance or resistance, with a favorable toxicity profile.

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Efficacy and Safety of Dasatinib in Patients with Chronic Myeloid Leukemia in Blast Phase Whose Disease Is Resistant or Intolerant to Imatinib: 2-Year Follow-Up Data from the START Program.

Blood ◽

10.1182/blood.v110.11.472.472 ◽

2007 ◽

Vol 110 (11) ◽

pp. 472-472 ◽

Cited By ~ 14

Author(s):

Carlo Gambacorti ◽

Jorge Cortes ◽

Dong-Wook Kim ◽

Herve Dombret ◽

Chao Zhu ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Poor Prognosis ◽

Blast Crisis ◽

Progression Free Survival ◽

Cytogenetic Response ◽

Prior Therapy ◽

Imatinib Resistant ◽

Grade 3

Abstract The prognosis for patients with myeloid-blast (MB) or lymphoid-blast (LB) chronic myeloid leukemia (CML) is poor, with an estimated survival from onset of blast crisis of approximately 3 months. Dasatinib (SPRYCEL®) is a novel inhibitor of BCR-ABL and SRC-family kinases, that has proven to be effective (in terms of complete hematologic and cytogenetic response) for patients with MB- or LB-CML whose disease is either resistant or intolerant to imatinib. Patients were enrolled to the corresponding START studies between January and June 2005, and dasatinib 70 mg BID was administered to 109 patients with MB-CML and 48 patients with LB-CML. All patients had previously failed treatment with imatinib - 90% of whom were resistant to imatinib. Here we present an update with a minimum follow-up of 12 mo. Of the 157 patients, 56% were male and median age was 54 years (range 17–81). Median time from CML diagnosis was 44 mo (range 2–216). Prior therapy included imatinib >600 mg/d in 50% of patients, treatment with imatinib for >3 years in 36%, and stem-cell transplantation in 19%. At baseline, 57% had WBC <20,000/mm3, 69% had platelets <100,000/mm3, and 18% had extramedullary disease outside of the spleen. Major hematologic responses (MaHRs) were induced in 34% of patients with MB-CML (imatinib-resistant 35%, -intolerant 20%) and 35% of LB-CML patients (imatinib-resistant 36%, -intolerant 33%). Major cytogenetic responses (MCyRs) were attained in 33% of patients with MB-CML (imatinib-resistant 34%, -intolerant 20%) and 52% of LB-CML patients (imatinib-resistant 50%, -intolerant 67%), while complete cytogenetic responses (CCyRs) were achieved in 26% (imatinib-resistant 26%, -intolerant 20%) and 46% of patients (imatinib-resistant 43%, -intolerant 67%), respectively. Median progression-free survival was 6.7 mo (MB-CML) and 3.0 mo (LB-CML) while median overall survival was 11.8 mo and 5.3 mo, respectively. Dasatinib was generally well tolerated in this poor prognosis population. Fluid retention events were observed more frequently in the MB-CML cohort, with all grade pleural effusion occurring in 36% and 13% of MB and LB patients, respectively (grade 3–4 - 15% and 6%). Other non-hematologic side effects were primarily grade 1–2. Cytopenias were noted for the majority of patients, and were manageable; grade 3–4 febrile neutropenia was recorded in 8% of patients. Dasatinib doses were reduced in 32% of patients and interrupted in 59%, most typically as a result of non-hematologic toxicities. Doses were escalated in 44% of patients. The median duration of therapy was 3.4 mo (0.03–18) for all patients and 14 mo (6–18) for patients still receiving treatment. Long-term data confirm that dasatinib is highly active, producing rapid and clinically meaningful responses in this poor prognosis patient population. Updated analyses corresponding to a minimum follow-up of 2 years on all patients will be presented.

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Phase 2 study of cemiplimab, a human monoclonal anti-PD-1, in patients (pts) with metastatic cutaneous squamous cell carcinoma (mCSCC; Group 1): 12-month follow-up.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.9526 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 9526-9526 ◽

Cited By ~ 12

Author(s):

Alexander David Guminski ◽

Annette May Ling Lim ◽

Nikhil I. Khushalani ◽

Chrysalyne D. Schmults ◽

Leonel Fernando Hernandez-Aya ◽

...

Keyword(s):

Antitumor Activity ◽

Adverse Events ◽

Median Duration ◽

Objective Response ◽

Locally Advanced ◽

Phase 2 ◽

Primary Analysis ◽

Phase 2 Study ◽

Grade 3

9526 Background: Primary analysis (Oct 2017) of cemiplimab (REGN2810) in pts with mCSCC in a Phase 2 study demonstrated substantial antitumor activity, durable responses, and acceptable safety profile. We now report 12-month follow-up data from these pts (NCT02760498; data cutoff date: Sep 20, 2018). Methods: Pts with mCSCC received cemiplimab 3 mg/kg IV every 2 weeks (Q2W). Tumor measurements were performed Q8W. The primary objective was to evaluate objective response rate (ORR; complete response [CR] + partial response [PR]) according to independent central review (per RECIST 1.1 for scans; modified WHO criteria for photos). Results: 59 pts (median age: 71 years) were enrolled. Median duration of follow-up was 16.5 months (range: 1.1–26.6). ORR by central review was 49.2% (95% CI: 35.9–62.5; 10 CRs and 19 PRs [4 CRs and 25 PRs by investigator-assessment (INV)]). Median duration of response (DOR) has not been reached. The longest DOR at data cut-off was 21.6 months and was still ongoing. Observed DOR exceeded 12 months in 22/29 pts (75.9%) with response. Durable disease control rate (stable disease or response for ≥16 weeks) was 62.7% (95% CI: 49.1–75.0). Median observed time to response was 1.9 months (range: 1.7–9.1). Median progression-free survival was 18.4 months (95% CI: 7.3–not evaluable); median overall survival has not been reached. The most common treatment-emergent adverse events (all grades, Grade ≥3) were diarrhea (28.8%, 1.7%), fatigue (25.4%, 1.7%), and nausea (23.7%, 0%). By INV, grade ≥3 immune-related adverse events occurred in 13.6% of pts. Conclusions: This analysis demonstrates substantial antitumor activity and increasing DOR with cemiplimab 3 mg/kg Q2W in pts with mCSCC. There were no new safety signals. These data strongly support the recent FDA approval of cemiplimab-rwlc for pts with mCSCC or locally advanced CSCC who are not candidates for curative surgery or curative radiation. Clinical trial information: NCT02760498.

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Phase 2 Study of Dasatinib in Chinese Patients (Pts) with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) or Advanced Phase Who Are Resistant to or Intolerant of Imatinib (IM)

Blood ◽

10.1182/blood.v118.21.4434.4434 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4434-4434

Author(s):

Jianxiang Wang ◽

Xiaojun Huang ◽

Jianda Hu ◽

Jianyong Li ◽

Jie Jin ◽

...

Keyword(s):

Pleural Effusion ◽

Median Time ◽

Philadelphia Chromosome ◽

Cytogenetic Response ◽

Phase 2 ◽

Efficacy And Safety ◽

First Line ◽

Phase 2 Study ◽

Grade 3

Abstract Abstract 4434 Background: CML has a lower incidence in China than in Western countries and appears to affect a younger population (Au, Int J Hematol 2009). In recent years, IM has become the first-line standard of care across Asia for pts with newly diagnosed CML. In a cohort of Chinese pts, >25% of evaluable pts in CP failed to achieve a CCyR with first-line IM, and response rates were significantly lower in pts with accelerated-phase (AP) or blast-phase (BP) CML (Wang, J Exp Clin Cancer Res 2010). Dasatinib is a highly potent second-generation BCR-ABL inhibitor that has established efficacy and safety in pts with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) after prior imatinib therapy. Dasatinib is approved by various regulatory authorities worldwide for first-line treatment of Philadelphia chromosome-positive (Ph+) CML in CP. Limited efficacy and safety data are available for second-generation BCR-ABL inhibitors in Chinese pts with CML or Ph+ ALL after imatinib therapy. Methods: In an open-label, single-arm phase 2 study, Chinese pts aged ≥18 years with IM resistant/intolerant CML or Ph+ ALL received dasatinib 100 mg once daily (CP) or 70 mg twice daily for AP/BP or Ph+ ALL. Bone marrow cytogenetic evaluation was performed at months 3 and 6, then every 6 months in CP pts, and was optional for pts with AP/BP or Ph+ ALL. Primary study objectives were to assess rates of major cytogenetic response (MCyR) in CP pts and complete and overall hematologic response (CHR and OHR) in pts with AP/BP or Ph+ ALL. OHR was defined as CHR, no evidence of leukemia, or return to CP. Treatment continued until disease progression or intolerable toxicity. Results: Of 140 enrolled pts, 121 pts had received ≥1 dose of dasatinib and were evaluable (59 with CP, 25 with AP, 35 with BP, and 2 with Ph+ ALL). Of pts with CML-CP or AP/BP/Ph+ ALL, 52 (88%) and 53 (85%) were IM resistant, 4 (7%) and 5 (8%) were IM intolerant, and 3 (5%) and 4 (6%) were both IM resistant and intolerant. Median time from original CML diagnosis to first dasatinib dose was 46.3 months (CP) and 50.2 months (AP/BP/Ph+ ALL). More than half of pts had received prior interferon therapy. At last follow-up, dasatinib therapy had been discontinued by 7 pts (12%) with CP and 43 pts (69%) with AP/BP/Ph+ ALL, due to disease progression or loss of response in 2% and 35%, study drug toxicity in 2% and 11%, stem-cell transplant in 0% and 5%, death in 2% and 2%, and other reasons in 7% and 16%, respectively. After a minimum of 12 months follow-up, MCyR was achieved by 30 pts with CP (51%), 10 pts with AP (40%), and 8 pts with BP/Ph+ ALL (22%). In pts with CP, median time to MCyR was 12 weeks and no patient lost MCyR. Complete cytogenetic response was achieved by 25 pts with CP (44%), 7 pts with AP (28%), and 6 pts with BP/Ph+ ALL (16%). CHR was achieved by 54 pts with CP (92%), 13 pts with AP (52%), and 6 pts (16%) with BP/Ph+ ALL. In CP pts, most (51/54) who achieved CHR did so within 2 months. Median times to CHR were 16 and 12 weeks for pts with AP and BP/Ph+ ALL, respectively. After 12 months, 3 pts in CP, 2 pts in AP, and 1 pt in BP had lost their CHR. OHR was achieved by 23 and 13 pts (92% and 35%) with AP and BP/Ph+ ALL, respectively. In safety assessments (Table), grade 3/4 cytopenia was frequent but managed by dose interruption/reduction or supportive care, with 1 pt discontinued for cytopenia. Pleural effusion of any grade occurred in 15%, 20%, and 22% of pts with CP, AP, and BP/Ph+ ALL, respectively. Grade 3/4 pleural effusion occurred in 1 pt with CML-CP (2%) and 5 pts with AP/BP/Ph+ ALL (8%). Conclusions: The current study confirms the efficacy and safety of dasatinib in Chinese pts with CML or Ph+ ALL that is resistant or intolerant to IM. Results were consistent with data from global trial populations. Disclosures: No relevant conflicts of interest to declare.

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Nilotinib in chronic myeloid leukemia patients in chronic phase (CML-CP) 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.7029 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 7029-7029

Author(s):

H. Kantarjian ◽

F. Giles ◽

K. Bhalla ◽

J. Pinilla ◽

R. A. Larson ◽

...

Keyword(s):

Myeloid Leukemia ◽

Total Bilirubin ◽

Chronic Phase ◽

Dose Intensity ◽

Cytogenetic Response ◽

Prior Therapy ◽

Day Range ◽

Biochemical Laboratory ◽

Secondary Endpoints

7029 Background: Nilotinib is a potent and highly selective BCR-ABL inhibitor approved for the treatment of Ph+ CML patients (pts) in CP or accelerated phase who are resistant or intolerant to prior therapy including IM. This study evaluated the efficacy and safety of nilotinib (400 mg bid) in CML-CP pts resistant or intolerant to IM. Methods: Primary endpoint was major cytogenetic response (MCyR). Secondary endpoints included complete cytogenetic response (CCyR), complete hematological response (CHR), MCyR duration, overall survival (OS), and safety. Results: CML-CP pts (n = 321, 70% IM-resistant, 30% IM-intolerant with resistance) with a minimum follow-up of 19 months (mos) were evaluated; 72% were treated with ≥600 mg/day IM prior to enrollment. Median duration of prior IM treatment was 32 (<1–94) mos. Median dose intensity of nilotinib (790 mg/day; range 151–1,110 mg/day) closely approximated the planned dose. Nilotinib led to rapid and durable CHR and MCyR. CHR was observed in 94% of pts. 59% achieved an MCyR (2.8 mos median time to MCyR; 56% in IM-resistant, and 65% in IM-intolerant pts), including 73% of pts with a baseline CHR and 44% achieved a CCyR (41% in IM-resistant; 51% in IM-intolerant pts). Responses were durable, with 78% pts maintaining MCyR at 24 mos. Estimated OS rate was 88% at 24 mos. Safety profile did not change with longer follow-up. Most frequent grade (gr) 3/4 biochemical laboratory abnormalities were elevated lipase (17%), hypophosphataemia (16%), hyperglycemia (12%), and total bilirubin (8%) which were transient and clinically asymptomatic. Gr 3/4 non-hematologic AEs were infrequent: rash, headache, and diarrhea occurred in 2% of pts. Most common gr 3/4 hematological laboratory abnormalities were neutropenia (31%), thrombocytopenia (31%), and anemia (10%). Brief dose interruptions were successful in management of most AEs. Pleural or pericardial effusions (gr 3/4) were uncommon (< 1%). Conclusions: These results demonstrate that nilotinib was highly effective, with rapid and durable responses in CML-CP pts failing prior therapy due to resistance or intolerance. Nilotinib was well tolerated with favorable risk/benefit. [Table: see text]

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Combination ibrutinib (Ibr) and venetoclax (Ven) for the treatment of mantle cell lymphoma (MCL): Primary endpoint assessment of the phase 2 AIM study.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.7520 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 7520-7520 ◽

Cited By ~ 7

Author(s):

Constantine Si Lun Tam ◽

Andrew Warwick Roberts ◽

Mary Ann Anderson ◽

Sarah-Jane Dawson ◽

Rodney J Hicks ◽

...

Keyword(s):

Primary Endpoint ◽

Phase Iii ◽

Phase 2 ◽

Prior Therapy ◽

Pet Ct ◽

Phase 2 Study ◽

Mantle Cell ◽

Starting Dose ◽

Grade 3

7520 Background: Both ibr and ven have activity in relapsed/refractory (R/R) MCL, but complete remissions (CR) are attained in <25% with either. We sought to determine the activity of the combination in an investigator-initiated, phase 2 study. Methods: Enrolment of 24 patients (pts) with R/R (n=23) or frontline (n=1) MCL completed in 09/16. Pts received 4 weeks of ibr (560mg/d), followed by introduction of ven (weekly ramp-up to target 400mg/d). The primary endpoint was CR rate at week 16, as assessed by PET/CT, BMAT, flow & molecular MRD, and endoscopy (if baseline gut involvement). Response was calculated separately with and without knowledge of the PET result by IWG criteria (Cheson JCO 2007), in order to compare with published studies (ibr, 9% CR at wk16; ven, best CR rate 21%). Results: Median age of pts was 68 (range, 47-81) years. For the R/R pts (n=23), median lines of prior therapy was 2 (1-6), 48% were refractory to last treatment, and 30% had failed previous autologous SCT. As of data cutoff on Jan 11 2017, 18 pts remain on therapy, and 6 stopped treatment due to progressive disease (4), adverse event (1) or unrelated death (1). At week 16, ORR was 71% (63% CR) and 80% of complete responders were flow-cytometry negative in the marrow (sensitivity 10-3 to 10-4). Using CT without PET, the comparison responses were CR 42%, CRu 17%, PR 17% (ORR 78%). After a median follow-up of 8.3 (range 1.4-17.7) months, the 8-month estimates of PFS and OS months are 74% and 81%. Adverse events ≥20%, irrespective of attribution, were fatigue (71%), diarrhea (67%), nausea (50%), URTI (38%), gastro-esophageal reflux (33%), neutropenia (33%), cough (25%) and bruising (21%); with the exception of neutropenia (25% grade 3-4), these were predominantly grade 1-2 in severity. Tumour lysis syndrome occurred in 2 pts with high tumour burden, leading to revision of the protocol ven starting dose from 50mg, to 20mg/d. Conclusions: The combination of ibr and ven was tolerable and achieved CR rate of 63% at week 16 in pts with MCL. The efficacy results compare favorably with historical results, and warrant further phase III investigation. Clinical trial information: NCT02471391.

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Phase 3 Study of Pomalidomide with Cyclophosphamide and Dexamethasone Versus Pomalidomide and Dexamethasone in Asian Patients with Relapsed/Refractory Myeloma (RRMM) - Interim Analysis of a Trial By the Asian Myeloma Network (AMN)

Blood ◽

10.1182/blood-2020-139019 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-1

Author(s):

Wee-Joo Chng ◽

Xinhua Li ◽

Cindy Lin ◽

Jin Seok Kim ◽

Hiroshi Handa ◽

...

Keyword(s):

Interim Analysis ◽

Research Funding ◽

Response Rate ◽

Prior Exposure ◽

Phase 2 ◽

Asian Patients ◽

Phase 2 Study ◽

Grade 3 ◽

Experienced Grade

Background Pomalidomide is an immunomodulatory drug that has been approved for the treatment of relapse refractory myeloma. A previous small randomized phase 2 study in the United States showed that combination of Pomalidomide, cyclophosphamide and dexamethasone induce a greater response rate than pomalidomide and dexamethasone1. In our prior study, AMN0012, we should that in patients with sub-optimal response to pomalidomide and dexamethasone, the addition of cyclophosphamide can increase response resulting in improvement of progression free survival. In the current study, we seek to randomize Asian patients with RRMM between PCD and PD to confirm the benefit of PCD. Method We conducted a prospective randomized trial of pomalidomide (4mg daily for 21 days followed by 7 days rest) plus dexamethasone 40mg once weekly for 4 weeks with or without cyclophosphamide (400mg once a week) in patients with relapse and refractory myeloma that has to be refractory to lenalidomide and has prior exposure to proteasome inhibitors. Each cycle is 4 weeks. Patients from Singapore, Japan and Korea (NCT03143049) were included in this Asian Myeloma Network trial. The trial was started in Sep 2017 and is still ongoing. To date, 53 patients have been recruited so far. This interim report presents data available up till the data cut-off date of 24 June 2020. Results Forty-six patients have available base line information and safety data and is included in this interim analysis. 50% of patients are male and median age of the cohort is 68 years old. 39% and 28% of patients are International Stage System (ISS) stage 2 and 3 respectively. 20% of patients have abnormal creatinine clearance. Median prior line of treatment is 3. All patients are refractory to lenalidomide and 96% have prior exposure to bortezomib. In addition, 12 patients (26%) and 5 (11%) have been treated with Carfilzomib and Ixazomib respectively. 15 (33%) patients had prior high dose melphalan and autologous stem cell transplant. 20 (44%) patients required dose reduction of pomalidomide, cyclophosphamide or dexamethasone. 89% of patients experience adverse events (AEs) of any grade. Of the 297 episodes of AEs, 43% are grade 3 or higher, with 50% of these episodes related to the study drugs. 57% of patients experienced serious AEs (SAEs) of any grade. Of the 74 episodes of SAE, 89% are grade 3 or higher, with 49% of these episodes related to the study drugs. Almost all of these events are related to cytopenias and infections. 20 (44%) of the patients develop grade 3 neutropenic fever and 9 (20%) patients have grade 3 or higher pneumonia. Only 1 patient experienced grade 3 peripheral neuropathy, 1 patient develop grade 3 pulmonary embolism, 1 patient developed grade 3 venous thromboembolism, and 1 patient experienced grade 3 renal impairment. At a median follow-up of 10.9 months, 9 of the 46 patients have died, and 21 have progressed. Three patients withdrew due to toxicity. While the overall response of the study population is not part of this interim analysis, we assessed the response of patients from the National University Cancer Institute, Singapore which has the highest number of patients recruited to get an idea of the therapeutic efficacy. Of the 14 patients recruited at NCIS, 1 patient achieved CR, 3 VGPR, 7 PR, producing a response rate of 79%. Conclusion In this interim analysis of a prospective randomized study of pomalidomide and dexamethasone with or without cyclophosphamide in Asian patients, we demonstrated the feasibility and efficacy of this combination. Longer follow-up and final analysis of the study will be needed to ascertain the therapeutic advantage of PCD over PD in relapse and refractory myeloma that is refractory to lenalidomide. References 1. Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. 2. Soekojo CY, Kim K, Huang SY, Chim CS, Takezako N, Asaoku H, Kimura H, Kosugi H, Sakamoto J, Gopalakrishnan SK, Nagarajan C, Wei Y, Moorakonda R, Lee SL, Lee JJ, Yoon SS, Kim JS, Min CK, Lee JH, Durie B,Chng WJ. 3. Pomalidomide and dexamethasone combination with additional cyclophosphamide in relapsed/refractory multiple myeloma (AMN001)-a trial by the Asian Myeloma Network. Blood Cancer J. 2019 Oct 8;9(10):83. Disclosures Chng: Novartis: Honoraria; Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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Bosutinib As Therapy for Chronic Phase Chronic Myeloid Leukemia Following Failure with Imatinib Plus Dasatinib and/or Nilotinib: 24-Month Minimum Follow-up Update

Blood ◽

10.1182/blood.v120.21.3785.3785 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3785-3785 ◽

Cited By ~ 1

Author(s):

H. Jean Khoury ◽

Carlo Gambacorti-Passerini ◽

Hagop M. Kantarjian ◽

Dong-Wook Kim ◽

David Marin ◽

...

Keyword(s):

Pleural Effusion ◽

Chronic Myeloid Leukemia ◽

Disease Progression ◽

Median Time ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Cytogenetic Response ◽

Grade 3

Abstract Abstract 3785 Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following TKI failure. A total of 119 pts aged ≥18 y with prior imatinib (IM) failure plus dasatinib (DAS) resistance (n = 38), DAS intolerance (n = 50), nilotinib (NIL) resistance (n = 27), NIL intolerance (n = 1), or failure of DAS and NIL (n = 3) received BOS starting at 500 mg/d. Median age was 56 y (range, 20–79 y); 45% of pts were male; median time from CML diagnosis was 6.5 y (range, 0.6–18.3 y). Median BOS duration was 8.6 mo (range, 0.2–60.8 mo); 24% of pts are still on treatment. Dose escalation to BOS 600 mg/d occurred in 19% of pts. Time from last pt's first dose to data cutoff was 25 mo (median follow-up duration of 31.4 mo [range, 0.3–66.0 mo]). A confirmed complete hematologic response (CHR) was attained/maintained by 73% of evaluable pts (Table). The Kaplan-Meier (KM) probability of maintaining a CHR at 2 y was 67%. A major cytogenetic response (MCyR) was attained/maintained by 41%, including 32% with a complete cytogenetic response (CCyR). Among evaluable pts without a baseline CCyR, 36% (n = 37/102) achieved a MCyR, including 28 (28%) with a CCyR. The KM probability of maintaining a MCyR at 2 y was 71%. Of 86 pts with baseline mutation status, 40 (47%) pts had 19 unique Bcr-Abl kinase domain mutations, including 7 (8%) pts with T315I. Responses were seen across mutations (75% CHR, 43% MCyR excluding T315I), including those conferring resistance to other TKIs; responses in pts with T315I were low (29% CHR; 14% MCyR). Nine of 37 pts evaluated at baseline and treatment discontinuation had ≥1 new mutation (V299L, n = 4; L248V, n = 2; T315I, n = 2; F359C, n = 1; G250E, n = 1); 8 of 9 pts had discontinued BOS due to disease progression or lack of efficacy. On-treatment transformation to accelerated phase CML occurred in 5 (4%) pts after 16 to 428 d on study; no pt transformed to blast phase CML. KM-estimated on-treatment progression-free survival (PFS) at 2 y was 75%; KM-estimated overall survival (OS) at 2 y was 84% (Table). There were 23 (19%) deaths on study, with 6 deaths occurring ≤30 d after the last BOS dose. Most deaths were due to disease progression (n = 10 [8%]) or an adverse event (AE; n = 10 [8%]; including 1 treatment-related death due to gastrointestinal bleeding). Three deaths were due to unknown cause ≥509 d after the last BOS dose. Non-hematologic treatment-emergent AEs (TEAEs) seen in ≥20% of pts (all grades; grade 3/4) included diarrhea (82%; 8%), nausea (49%; 1%), vomiting (40%; 1%), rash (27%; 3%), headache (26%; 3%), fatigue (24%; 1%), and abdominal pain (20%; 1%). The incidence of individual TEAEs was generally similar across groups regardless of prior TKI exposure. Diarrhea TEAEs were predominantly grade 1/2, first reported early during treatment (median time to first event of 1.5 d [range, 1–210 d]), and transient (median event duration of 2 d [range, 1–524 d]). The incidence of pleural effusion was highest among DAS-intolerant pts (n = 11 [22%], including 3 pts with grade 3 events); for 9 of 11 pts pleural effusion had been indicated as a reason for intolerance to prior DAS. Grade 3/4 laboratory abnormalities reported in ≥10% of pts included thrombocytopenia (25%), neutropenia (19%), lymphopenia (17%), and hypermagnesemia (12%). Dose reductions and interruptions were used to manage AEs in 50% and 66% of pts. A total of 32 (27%) pts discontinued treatment due to an AE, most commonly hematologic events. In conclusion, BOS therapy continues to demonstrate durable efficacy and manageable toxicity after follow-up of ≥24 mo in CP CML following resistance or intolerance to multiple TKIs, with a majority of pts maintaining response at 2 y and few new transformations, deaths, TEAEs, or discontinuations due to AEs since the prior report ∼1 y earlier (Blood 2012;119:4303–12). n (%) IM + DAS-R IM + DAS-I IM + NIL-R IM + DAS ± NILa Total Evaluableb 37 49 25 4 115 CHR 23 (62) 39 (80) 19 (76) 3 (75) 84 (73) Evaluableb 36 44 26 4 110 MCyR 12 (33) 21 (48) 10 (39) 2 (50) 45 (41) CCyR 7 (19) 19 (43) 7 (27) 2 (50) 35 (32) Treated 38 50 27 4 119 PFS at 2 yc 70% 81% 79% 38% 75% OS at 2 yc 77% 85% 92% 75% 84% R, resistant; I, intolerant. a Includes 3 pts with prior exposure to all 3 TKIs and 1 NIL-I pt. KM rates may be unreliable due to the small number of pts in this cohort. b Received ≥1 dose of BOS and had a valid baseline response assessment. c Based on KM estimates Disclosures: Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Kantarjian:Pfizer: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marin:Novartis: Research Funding; BMS: Research Funding. Dorlhiac-Llacer:Novartis, Bristol Myer Squibb, Pfizer: Research Funding. Bullorsky:Novartis, BMS: Consultancy, Speakers Bureau. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Turnbull:Pfizer Inc, l3/Inventiv Clinical Solutions: Employment. Besson:Pfizer Inc: Employment. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding.

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Update on KEYNOTE-199, cohorts 1-3: Pembrolizumab (pembro) for docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.104 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 104-104 ◽

Cited By ~ 2

Author(s):

Emmanuel S. Antonarakis ◽

Josep M. Piulats ◽

Marine Gross-Goupil ◽

Jeffrey C. Goh ◽

Ulka N. Vaishampayan ◽

...

Keyword(s):

Antitumor Activity ◽

Response Rate ◽

Phase 2 ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Phase 2 Study ◽

Previously Treated ◽

Grade 3 ◽

Clinical Trial Information

104 Background: The KEYNOTE-199 multicohort phase 2 study (NCT02787005) showed that pembro monotherapy has antitumor activity and acceptable safety in patients (pts) with mCRPC previously treated with a next-generation hormonal agent (NHA) and docetaxel in cohort 1 (C1) (RECIST-measurable, PD-L1+ disease), C2 (RECIST-measurable, PD-L1− disease), and C3 (bone-predominant disease, irrespective of PD-L1). Updated results with additional follow-up for C1-3 are presented. Methods: Pts previously received ≥1 NHAs and 1 or 2 chemotherapies, including docetaxel. Pts received pembro 200 mg Q3W for 35 cycles or until progression or intolerable toxicity. Primary end point was ORR. Key secondary end points were DCR, DOR, PSA (≥50%) response rate, rPFS, OS, and safety. Results: Of 258 pts enrolled (C1=133; C2=67; C3=58), 6 completed (C1=4; C3=2) and 252 discontinued (C1=129; C2=67; C3=56) therapy, primarily due to progression (C1=106; C2=61; C3=45). Median follow-up was 9.6 mo (C1, 9.5; C2, 7.9; C3, 14.2). ORR (95% CI) for pts with measurable disease was 6% (2.6-11.5) in C1 and 3% (0.4-10.4) in C2 (Table; includes other efficacy results). Treatment-related AEs of any grade/grade 3-5 occurred in 57%/16% in C1, 60%/15% in C2, and 71%/17% in C3. 1 pt in each cohort died of a treatment-related AE (C1, sepsis; C2, unknown; C3, immune-related pneumonitis). Conclusions: With additional follow-up, pembro monotherapy continued to show antitumor activity and disease control in pts with RECIST-measurable and bone-predominant mCRPC previously treated with both NHA and docetaxel. Pts experienced durable responses. Safety was consistent with the known safety profile of pembro. Clinical trial information: NCT02787005. [Table: see text]

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Phase 2 Study of Nilotinib 400 Mg Twice Daily in Newly Diagnosed Patients with Accelerated Phase of Chronic Myeloid Leukemia, Results after 5.7 Years of Follow-up

Blood ◽

10.1182/blood-2018-99-120155 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3011-3011 ◽

Cited By ~ 1

Author(s):

Lucia Masarova ◽

Jorge E. Cortes ◽

Keyur P. Patel ◽

Susan M. O'Brien ◽

Graciela M. Nogueras González ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Phase 2 ◽

Advisory Committees ◽

Free Survival ◽

Genetics Research ◽

Phase 2 Study ◽

Grade 3

Abstract OBJECTIVES Nilotinib is a potent, second generation inhibitor of BCR-ABL tyrosine kinase (TKI) and represent a standard of care for patients with chronic myeloid leukemia (CML), including accelerated phase (AP-CML). In 2005, we initiated a phase 2 study of nilotinib 400 mg twice daily as a frontline therapy in patients with AP-CML, and herein present the efficacy and safety data after a median follow-up of 68.4 months (range, 0.3-124.8). METHODS This was a prospective, single institution, phase 2 study in patients of age ≥18 years with a newly diagnosed, untreated AP-CML (except for <1 month of previous imatinib) defined according to MD Anderson criteria (Kantarjian, 1988). Patients were treated with nilotinib 400 mg twice daily (BID). Data are presented on an intention to treat analysis with a cutoff date of June 30st, 2018. Response criteria are standard. Fisher exact test and χ2 were used for analysis of categorical variables; and survival probabilities were estimated using the Kaplan-Meier method. Time to events (e.g., overall survival, event free survival) was calculated from the date of treatment to the date of an event or to last follow-up as previously reported (Cortes et al, 2010). RESULTS Twenty two patients of a median age of 53.7 years (range, 26-79.7) were enrolled. Table 1 summarizes clinical characteristics of all patients. The median treatment duration was 47.3 months (range; 0.3-124.4), and the median follow-up 68.4 months (range, 0.3-124.8). All patients discontinued study as of January 2017 due to planned study closure; but 11 patients (50%) continued on nilotinib off protocol at data cut-off (400 mg BID [3]; 300 mg BID [2]; and 200 mg BID [6]). Median time to treatment discontinuation in the remaining 11 patients was 12.9 months (range, 0.3-112); reason for discontinuation was: inadequate response [3], toxicity [2], non-compliance/financial [4]; elective discontinuation after sustained MR4.5 >2 years [1]; and death due to stroke [1]. Sixteen patients (73%) achieved complete hematologic response (CHR). Overall rates of CCyR, MMR, MR4.5 and CMR (undetectable transcripts with at least 100,000 ABL copies) were 73%, 73%, 55%, and 41%, respectively. Median times to CCyR, MMR, and MR4.5 were 2.9 months (range, 2.7-6.4), 5.7 months (range, 2.7-99.2) and 6.0 months (range, 2.7-36), respectively. Seven patients (32%) achieved sustained MR4.5 >2 years. In total, 4 patients lost their best achieved response (CHR [1], CCyR [2] and MR4.5 [1]) while on study. All events were associated with acquired ABL domain mutation; Y253H [2], T315I [1], and F359I [1] with a median time to detection of 16.7 months (range, 7-40). During the study conduct, one patient progressed to blast phase after 2 months on nilotinib. Two patients died while on study, one due to stroke and one due to unrelated medical condition, after being on therapy for 3 and 0.4 months, respectively. One patient electively discontinued nilotinib after being in sustained MR4.5 for 107 months, and remains in MR4.5 after 6 months off therapy. Estimated overall survival and event free survival at 5 years were 84% and 70%, respectively (Figures 1a & 1b). On univariate analysis, age >55 years was associated with lower rate of MMR (p = 0.034; HR 0.34; 95% CI 0.12-0.92); MR4 (p = 0.013; HR 0.25; 95% CI 0.08-0.75); and MR4.5 (p = 0.01; HR 0.15; 95% CI 0.04-0.63). Overall survival was inferior in patients older than 55 years (p = 0.014; HR 2.4; 95% CI 2.36-not estimated); and in those with > 1 AP-CML defining abnormality (p = 0.018; HR 9.53; 95% CI 0.98-92). The most frequent non-hematologic adverse events (AEs) were hyperbilirubinemia (63% of patients), rash (63%), hypertension (59%), and transaminitis (50%). Grade ≥3 AEs observed in more than one patient were hyperbilirubinemia (n=2), and transaminitis (=2). Two patients developed arterio-thrombotic AEs: stroke and myocardial infarction (one each). Hematologic AEs included (all grades; grade ≥3): anemia (36%; 9%), thrombocytopenia (32%; 14%) and neutropenia (14%; 9%). Two patients (9%) discontinued therapy due to nilotinib related AE, one for G3 peripheral neuropathy and one for G3 hyperbilirubinemia with G2 thrombocytopenia. CONCLUSION Nilotinib is safe and highly effective in patients with AP-CML, and induces fast and durable responses. More than 50% of patients can achieve MR4.5. Clinical trial.gov: NCT00129740. Disclosures Cortes: novartis: Research Funding. O'Brien:Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Kite Pharma: Research Funding; Regeneron: Research Funding; Vaniam Group LLC: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Alexion: Consultancy; Abbvie: Consultancy; GlaxoSmithKline: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Astellas: Consultancy; TG Therapeutics: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding; Immunogen: Research Funding; abbvie: Research Funding; cellectis: Research Funding. Verstovsek:Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kadia:Celgene: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Novartis: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Seattle Genetics: Research Funding.

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