Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma

Purpose No standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 ( FGFR2) fusions/translocations are present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. Methods A multicenter, open-label, phase II study ( ClinicalTrials.gov identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age ≥ 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. Patients received BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles). The primary end point was investigator-assessed overall response rate. Results Sixty-one patients (35 women; median age, 57 years) with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) participated. At the prespecified data cutoff (June 30, 2016), 50 patients had discontinued treatment. All responsive tumors contained FGFR2 fusions. The overall response rate was 14.8% (18.8% FGFR2 fusions only), disease control rate was 75.4% (83.3% FGFR2 fusions only), and estimated median progression-free survival was 5.8 months (95% CI, 4.3 to 7.6 months). Adverse events included hyperphosphatemia (72.1% all grade), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%). Grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%) and included hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). Conclusion BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions. This promising antitumor activity supports continued development of BGJ398 in this highly selected patient population.

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Phase II Study of Lenvatinib in Patients With Progressive, Recurrent or Metastatic Adenoid Cystic Carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.18.01859 ◽

2019 ◽

Vol 37 (18) ◽

pp. 1529-1537 ◽

Cited By ~ 22

Author(s):

Vatche Tchekmedyian ◽

Eric J. Sherman ◽

Lara Dunn ◽

Crystal Tran ◽

Shrujal Baxi ◽

...

Keyword(s):

Adverse Events ◽

Adenoid Cystic Carcinoma ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Progression Free Survival ◽

Free Survival ◽

Overall Response ◽

End Point ◽

Adenoid Cystic

PURPOSE Recurrent or metastatic adenoid cystic carcinoma (R/M ACC) is a malignant neoplasm of predominantly salivary gland origin for which effective therapies are lacking. We conducted a phase II trial evaluating the multitargeted tyrosine kinase inhibitor lenvatinib in patients with R/M ACC. PATIENTS AND METHODS This study was conducted with a two-stage minimax design. Patients with histologically confirmed R/M ACC of any primary site with radiographic and/or symptomatic progression were eligible. Any prior therapy was allowed except previous lenvatinib. Patients received lenvatinib 24 mg orally per day. The primary end point was overall response rate. Secondary end points were progression-free survival and safety. An exploratory analysis of how MYB expression and genomic alterations relate to outcomes was conducted. RESULTS Thirty-three patients were enrolled; 32 were evaluable for the primary end point. Five patients (15.6%) had a confirmed partial response, 24 patients (75%) had stable disease, two patients (6.3%) discontinued treatment as a result of toxicity before the first scan, and one patient (3.1%) had progression of disease as best response. Median progression-free survival time was 17.5 months (95% CI, 7.2 months to not reached), although only eight progression events were observed. Patients otherwise were removed for toxicity (n = 5), as a result of withdrawal of consent (n = 9), or at the treating physician’s discretion (n = 6). Twenty-three patients required at least one dose modification, and 18 of 32 patients discontinued lenvatinib for drug-related issues. The most common grade 3 or 4 adverse events were hypertension (n = 9; 28.1%) and oral pain (n = 3; 9.4%). Three grade 4 adverse events were observed (myocardial infarction, n = 1; posterior reversible encephalopathy syndrome, n = 1; and intracranial hemorrhage, n = 1). CONCLUSION This trial met the prespecified overall response rate primary end point, demonstrating antitumor activity with lenvatinib in R/M ACC patients. Toxicity was comparable to previous studies, requiring monitoring and management.

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Sorafenib With Interferon Alfa-2b As First-Line Treatment of Advanced Renal Carcinoma: A Phase II Study of the Southwest Oncology Group

Journal of Clinical Oncology ◽

10.1200/jco.2007.11.1047 ◽

2007 ◽

Vol 25 (22) ◽

pp. 3296-3301 ◽

Cited By ~ 124

Author(s):

Christopher W. Ryan ◽

Bryan H. Goldman ◽

Primo N. Lara ◽

Philip C. Mack ◽

Tomasz M. Beer ◽

...

Keyword(s):

Adverse Events ◽

Phase Ii ◽

Renal Carcinoma ◽

Response Rate ◽

Kinase Inhibitor ◽

Phase Ii Study ◽

Performance Status ◽

Combined Treatment ◽

Progression Free Survival ◽

Interferon Alfa

Purpose This phase II study evaluated the activity of combined treatment with interferon alfa-2b and sorafenib, a Raf and multiple receptor tyrosine kinase inhibitor, in patients with advanced renal carcinoma. Patients and Methods Eligible patients had metastatic or unresectable renal carcinoma with a clear-cell component, no prior systemic therapy, performance status 0 to 1, and measurable disease. Treatment consisted of interferon alfa-2b 10 × 106 U subcutaneously three times weekly and sorafenib 400 mg orally bid. The primary end point was confirmed Response Evaluation Criteria in Solid Tumors response rate. Results Twelve (19%) of 62 assessable patients achieved an objective confirmed response. An additional 31 (50%) had an unconfirmed partial response or stable disease as best response. The median progression-free survival was 7 months (95% CI, 4 to 11 months). The most common adverse events were fatigue, anorexia, anemia, diarrhea, nausea, rigors/chills, leukopenia, fever, and transaminase elevation. Von Hippel-Lindau gene mutations were detected in four (22%) of 18 archival tumor specimens. Conclusion The confirmed response rate for the combination of sorafenib and interferon in advanced renal carcinoma is greater than expected with either interferon or sorafenib alone. The toxicity of this combination is dominated by adverse events common to interferon that limit further development of this regimen.

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Randomized Phase II Study of Combined Epigenetic Therapy: Decitabine Vs. Decitabine and Valproic Acid in MDS and AML

Blood ◽

10.1182/blood.v112.11.228.228 ◽

2008 ◽

Vol 112 (11) ◽

pp. 228-228 ◽

Cited By ~ 12

Author(s):

Jean-Pierre Issa ◽

Ryan Castoro ◽

Farhad Ravandi-Kashani ◽

Stefan Faderl ◽

Xuelin Huang ◽

...

Keyword(s):

Dna Methylation ◽

Valproic Acid ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Study ◽

Epigenetic Therapy ◽

Overall Response ◽

First Response ◽

Randomized Phase Ii

Abstract Introduction: Inhibition of DNA methylation (DNMTi) by decitabine (DAC) or azacitidine is a form of epigenetic therapy that is clinically effective in the treatment of MDS and AML. In-vitro, histone deacetylase inhibition (HDACi) following DNA hypomethylation induction results in synergistic enhancement of gene expression activation, but the effects of HDACi on the cell cycle can also interfere with DNTMi activity, resulting in schedule dependent antagonism. Phase I/II studies of the combination of DNMTi and HDACi have shown some promise, triggering randomized studies. Methods: We conducted a randomized phase II study of DAC at 20 mg/m2 IV/1 hour daily ×5 q4 weeks vs. DAC at a similar dose + Valproic acid (VPA) 50 mg/kg PO daily ×7 starting on day 1 of DAC. Eligibility included MDS (FAB), IPSS>0 or AML, age >60 (excluding APL and CBF AML). An adaptive randomization design based on a composite score of CR, response and survival was used after the 40th patient to assign patients to the superior arm. DNA methylation was measured by bisulfite pyrosequencing on peripheral blood mononuclear cells prior to and during treatment. Results: 76 patients were enrolled on the study, 2 of whom received no therapy and are excluded from analysis. These included 8 patients with CMML (median age 72), 23 patients with AML (median age 71 (63–81), median BM blasts 40% (30–87), median WBCs 5.4 (1.1–97)) and 43 patients with MDS (median age 66 (36–89), IPSS Int1 (10), Int2 (19) and high (14)). Cytogenetics were abnormal in 40 patients (54%), most with complex or poor risk karyotypes. 42 patients (57%) were randomized to DAC alone. Overall, the median number of courses given so far is 4 (1–17) and 27 patients (36%) remain on therapy, at a median follow-up of 14 months. Response data are available for 67 patients (7 are too early). Overall, responses were seen in 31 patients (46%), with CR in 23 (34%) and other responses in 8 (12%). Overall response rate was 39% in AML, 71% in CMML and 46% in MDS. In patients receiving decitabine alone, the overall response rate was 17/40 (43%), compared to 14/27 (52%) in those randomized to DAC+VPA (p=NS). Median time to first response was 64 days (18–194) with DAC alone compared to 57 days (23–123) with DAC+VPA (p=NS). VPA added significant neurotoxicity to the regimen, with several patients discontinuing the drug due to somnolence or confusion. Median survival was 8.7 months in AML and 14.9 months in MDS (p=0.04). Kaplan-Meier analysis showed no difference in survival between DAC and DAC+VPA in the first year after therapy. DNA methylation analysis showed a similar degree of LINE demethylation in both arms, Conclusions: Preliminary analysis of this randomized study suggests that adding VPA to DAC only marginally improves response rate and time to first response and has no impact on survival in MDS and AML. It remains to be seen (in randomized studies) whether more potent HDACi will show greater evidence of clinical synergy with DNMTi.

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Phase II Study of the Histone Deacetylase Inhibitor Panabinostat (LBH589) in Patients with Low or Intermediate-1 Risk Myelodysplastic syndrome

Blood ◽

10.1182/blood.v118.21.1731.1731 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1731-1731

Author(s):

Sophie Dimicoli ◽

Elias Jabbour ◽

Gautam Borthakur ◽

Tapan Kadia ◽

Zeev Estrov ◽

...

Keyword(s):

Adverse Events ◽

Phase Ii ◽

Median Duration ◽

Lower Risk ◽

Response Rate ◽

Phase Ii Study ◽

Single Agent ◽

Clinical Activity ◽

Number Of Patients ◽

Deacetylase Inhibitor

Abstract Abstract 1731 Panabinostat is a very potent panhistone deacetylase inhibitor (HDACi) with activity in acute myelogenous leukemia (CCR 2006;12: 4628). We hypothesized that single agent panabinostat could be active in patients with low and intermediate-1 risk MDS. Oral route of administration and safety profile further increased interest in this approach. To test this concept we designed a phase II study of panabinostat for patients above 18 years of age with lower risk disease. Patients could have received prior therapy or be treatment naïve. Appropriate renal, hepatic and cardiac functions were required. Patients were excluded if they had previous HDACi treatment. Patients with history of cardiac pathology such as rhythm alterations were excluded from the study. Use of drugs that could induce QT prolongation and CYP3A4 inhibitors were not allowed. Panabinostat was used at dose of 20 mg orally three times a week for consecutive 3 weeks with cycles repeated every 4 weeks. The primary objective of the study was overall response rate defined by IWG. A maximum of 40 patients could be enrolled. The study was to stop early if the expected response rate was less than 15%. Stopping rules were as follows: Stop if the number of patients with hematologic improvement/the number of patients evaluated was 0/15 or 1/32. The study also contained a stopping rule for non-hematological toxicity. Thirteen patients were enrolled between August 2009 and December 2010. Median age was 70 years (range 47 to 84, 84% of patients older than 60), 70% were transfusion dependent, 70% had intermediate-1 risk MDS, most patients were diploid but one patient with del(5q), one with trisomy 8, one with complex cytogenetics and 2 with deletion of 20q were included. Median percent of marrow blasts was 1% (range 1 to 6%). At start of therapy, median hemoglobin was 9.5 (range 7.5–11.2 G/dL), median platelet count was 56 (range 6–431 k/uL) and median white blood cell count was 4.6 (range 0.8–20.3 k/uL). Approximately 40% had previous therapy for MDS including hypomethylating agents, lenalidomide and investigational agent. Median number of prior therapies for treated patients was 2 (range 1 to 4). Median duration of disease at time of enrollment was 10 months (range 1–50). Patients received a median of 4 cycles of panabinostat (range 1–9). Of 13 patients, 1(8%) achieved a hematological improvement including both an erythroid and platelet response that lasted for 3 months. No complete remissions or partial responses were documented. Six patients (46%) had stable disease for a median duration of 6 months (range 2–13.6). Median overall survival was 15 months (1–31 months). Two patients died because progression to AML. Therapy was well tolerated: no major adverse events were documented except for one patient that developed significant QTc prolongation. Adverse events included mild fatigue and gastrointestinal toxicity. As a biomarker of molecular activity, histone H3 acetylation was measured in 5 patients with variable results. Induction of acetylation was documented in 2. Despite the fact that the stopping rule for activity was not officially met, because of the very modest clinical activity observed, the study was closed to new patient entry. In conclusion, panabinostat given as a single agent orally at a dose of 20 mg thee times a week for 3 weeks followed by one week of rest has limited clinical activity in patients with lower risk MDS. Disclosures: No relevant conflicts of interest to declare.

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Phase II study of PX-866 in recurrent glioblastoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2053 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2053-2053 ◽

Cited By ~ 3

Author(s):

Marshall W. Pitz ◽

Elizabeth A. Eisenhauer ◽

Mary Valeria MacNeil ◽

Brian Thiessen ◽

David R. Macdonald ◽

...

Keyword(s):

Phase Ii ◽

Stable Disease ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Study ◽

Performance Status ◽

Recurrent Glioblastoma ◽

Pik3ca Mutations ◽

Overall Response ◽

Grade 3

2053 Background: Glioblastoma (GBM) is the most aggressive malignancy of the central nervous system. The majority have genetic changes that increase the activity of the phosphatidylinositol-3-OH kinase (PI3K) signal transduction pathway, critical for cell motility, proliferation, and survival. We present the results of PX-866, an oral PI3K inhibitor, in patients (pts) with recurrent GBM. Methods: A multinomial design of response and early progression (< 8 weeks on study) was used. In stage 1 (15 pts), 0 responses and ≥ 10 early progressions would stop accrual; after full accrual, ≥ 4 responses OR ≤ 13 early progressions was prespecified as of interest. Pts with histologically confirmed GBM, at first recurrence after chemoradiation and adjuvant temozolomide were given PX-866 8 mg daily on this single-arm phase II study. MRI and clinical exam were done every cycle (8 weeks). Tumour tissue was collected for analysis of potential markers of PI3K inhibitory activity (PTEN, EGFRviii, PIK3CA mutations). Results: A total of 33 pts were enrolled, eligible and evaluable. Median age was 56 (range 35-78), 12 were female; 29 had performance status (PS) 0-1 and 4 had PS 2. Median time from initial diagnosis to enrolment was 308 days (range 141-1256). Median number of cycles was 1 (range 1-7). Thirty-two pts have discontinued therapy, 26 due to disease/symptomatic progression and 6 due to toxicity (5 LFT elevation and 1 allergic reaction). Other adverse effects (AE): fatigue (16 pts/2 grade 3), diarrhea (11 pts/5 grade 3), nausea (19 pts/1 grade 3), vomiting (11 pts/1 grade 3) and lymphopenia (29 pts/7 grade 3/4). Five pts had related serious AEs (1 LFTs, 1 GI and 3 venous thromboembolism) All pts were evaluable for response; 25 had a best response of progression, 1 had partial response (overall response rate 3%) and seven (21%) had stable disease (SD, median 7.3 months; range 3.1-13.6). Six month PFS was 17%. In preliminary analyses, no statistical association was found between SD and PTEN or EGFRviii status (results pending in 16 pts). Conclusions: PX-866 was relatively well tolerated. Overall response rate was low, and the study did not meet its primary endpoint; however, 21% of pts obtained durable stable disease. Further correlative work is required to identify the predictor of this effect. Clinical trial information: NCT01259869.

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Phase II study of sequential S-1 and cyclophosphamide therapy in patients with metastatic breast cancer

10.21203/rs.3.rs-22934/v1 ◽

2020 ◽

Author(s):

Keiko Yanai ◽

Takaaki Fujii ◽

Jun Horiguchi ◽

Yuko Nakazawa ◽

Sasagu Kurozumi ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Adverse Events ◽

Phase Ii ◽

Phase Ii Study ◽

Metastatic Breast ◽

Progression Free Survival ◽

Sequential Therapy ◽

Open Label ◽

Overall Response

Abstract Purpose: S-1 and cyclophosphamide (CPA) can be given orally, and their combination may have great potential for treating metastatic breast cancer (MBC). A phase I study of sequential S-1 and CPA therapy was conducted in patients with MBC; the recommended doses that were determined for this regimen were 80 mg/m 2 /day for S-1 and 100 mg/m 2 /day for CPA. We then conducted a phase II study of this oral S-1 and CPA regimen. Patients and Methods: This was a single-arm, open-label, single-center prospective phase II study to evaluate the efficacy of a sequential S-1 and CPA regimen for MBC. S-1 was administered orally 2´/day for 14 consecutive days, and then CPA was administered orally 1´/day for 14 consecutive days in a repeating 4-week cycle (S-1 for 2 weeks, CPA for 2 weeks). The primary endpoint was the overall response rate (ORR). Secondary endpoints included the overall survival (OS), progression-free survival (PFS), clinical benefit rate (CBR) and safety. Results: Thirty-six patients were enrolled in this study. The overall response was complete response in 0 (0%), partial response in 12 (33.3%), stable disease in 12 (33.3%), and progressive disease in 11 (30.1%) patients. The ORR was 33.3% (12/36). The CBR was 66.7% (24/36). The mean PFS was 9.5 months (95%CI: 7.1–11.9 months). The OS was 20.2 months (95%CI: 15.0–25.6 months) Grade 3/4 adverse events included neutropenia in seven patients (19.4%). Dose reductions because of adverse events occurred in 12 patients (33.3%). There was no treatment-related mortality. Conclusion: The combination of sequential therapy with S-1 and CPA was tolerable and had efficacy with good disease control. Sequential therapy with S-1 and CPA is a feasible new treatment option for patients with MBC.

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Cetuximab plus docetaxel-cisplatin (DC) as first-line treatment for locally advanced or metastatic gastric cancer: Preliminary results of a phase II study

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15592 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15592-e15592

Author(s):

J. Fahlke ◽

K. Ridwelski ◽

A. Florschuetz ◽

E. Kettner ◽

M. Leithaeuser ◽

...

Keyword(s):

Gastric Cancer ◽

Disease Progression ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Study ◽

Published Data ◽

First Line ◽

Overall Response ◽

Grade 3

e15592 Background: Based on promising published data, this multicenter, phase II study was initiated to investigate a combined treatment using DC and cetuximab in the first-line setting for patients with gastric cancer. Methods: Patients aged 18–75 years with stage III (T4, nonresectable) or stage IV gastric cancer, ECOG performance status (PS) ≤2, and life expectancy ≥3 months were recruited to receive cetuximab (400 mg/m2 on day 1 then 250 mg/m2 q1w) and DC (D 75 mg/m2 and C 75 mg/m2; both as 1-h infusions on day 1 and then q3w). Treatment was stopped in the event of disease progression, intolerable toxicity, or consent withdrawal. Tumor staging was performed after cycle 3 and then every 12 weeks. The primary endpoint was overall response rate and secondary endpoints included time to progression, overall survival and toxicity. Planned accrual was 79 patients. A per-protocol interim response analysis was planned for the initial 20 evaluable patients. Results: Preliminary data are available for 30 patients; median age 64 [range: 40–73] years; median ECOG PS 1 [range: 0–2]; adenocarcinoma 87%. Median cycles administered were 3 [range: 1–14] and the median follow-up was 1.63 months. The overall response rate was 27.3% (complete response, n=1; partial response, n=5). Stable disease was observed in 10 patients, and disease progression in 6 patients. The most relevant NCI-CTC grade 3–4 hematologic events per patient were leukopenia and neutropenia (73%), anemia (13%), and febrile neutropenia (10%). Major grade 3–4 nonhematologic toxicities were nausea (30%), vomiting (20%), diarrhea (13%), acne (13%), and fatigue (13%). Conclusions: DC and cetuximab were well tolerated and resulted in promising response rates and a predictable toxicity profile. The study is ongoing. No significant financial relationships to disclose.

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Phase II study of afatinib in recurrent and/or metastatic esophageal squamous cell carcinoma (R/M ESCC) (KCSG HN14-18).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.4051 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 4051-4051

Author(s):

Min Hee Hong ◽

Yun-Gyoo Lee ◽

Hyo Song Kim ◽

Keon Uk Park ◽

Hoon-Gu Kim ◽

...

Keyword(s):

Phase Ii ◽

Response Rate ◽

Kinase Inhibitor ◽

Phase Ii Study ◽

Clinical Investigation ◽

Objective Response ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

Open Label ◽

Platinum Based Chemotherapy

4051 Background: Afatinib, an irreversible pan-ErbB kinase inhibitor showed anti-tumor activity against esophageal cancer in phase I trial. In this multicenter, open-label, single arm phase II study, we aimed to evaluate the activity and safety of afatinib in R/M ESCC. Methods: Patients (pts) who had ECOG PS 0-2 and had progressed on platinum-based chemotherapy for R/M ESCC were enrolled. Pts were treated with afatinib 40mg/day until disease progression, unacceptable toxicity, or patient’s refusal. Primary endpoint was objective response rate (ORR) per RECIST 1.1. The estimated sample size was 49, using a two-stage minimax design to evaluate incremental response rate from 5 to 15%. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety profile. Additionally, we try to identify biomarker to predict efficacy of afatinib with target capture sequencing and gene expression profile as exploratory endpoints. Results: In a total of 49 enrolled pts (median age 60; range 44 -84), ORR and DCR were 14.3 % and 73.3%, respectively. With a median follow-up of 6.6 months, median PFS and OS was 3.4 months (95% CI 2.2-4.6) and 6.6 months (95% CI 5.2-8.0). Median treatment duration and duration of response were 2.8 months (range, 0.4-15.3) and 7.1 months (range, 2.5-13.9), respectively. Dose reduction and interruption occurred in 19 (38.8%) and 15 (30.6 %) pts. Treatment-related adverse events (TRAE) occurred in 33 pts (67.3%) with most common TRAEs being diarrhea (n=22, 44.9%) and acneiform rash (n=12, 24.5%). G3-4 TRAEs were rare, occurring in 7 pts (14.3 %). Conclusions: Afatinib demonstrated modest efficacy with manageable toxicity in platinum-resistant R/M ESCC patients. Given the modest response rate, identification of predictive biomarkers is essential for further clinical investigation of afatinib in R/M ESCC. Those biomarkers are being analyzed and will be presented in the conference (NCT02353936). Clinical trial information: NCT02353936. [Table: see text]

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Treatment free remission (TFR) and overall response rate (ORR) results in patients with relapsed/refractory Waldenstrom’s macroglobulinemia (WM) treated with CLR 131.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.7561 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 7561-7561

Author(s):

Sikander Ailawadhi ◽

Asher Alban Akmal Chanan-Khan ◽

Jennifer Layton Peterson ◽

Jarrod Longcor ◽

Katherine Oliver ◽

...

Keyword(s):

B Cell ◽

Median Time ◽

Overall Response Rate ◽

Response Rate ◽

Kinase Inhibitor ◽

Primary Objective ◽

Open Label ◽

B Cell Malignancies ◽

Overall Response ◽

Treatment Free Remission

7561 Background: Phospholipid ethers (PLE) provide a novel mechanism to specifically target tumor cells leveraging high lipid raft content in their cell membranes. PLE/phospholipid drug conjugates are specifically designed to have high affinity to lipid rafts which upon binding results in trans-membrane flipping with the ability to deliver an attached warhead directly to the cytosol. CLR 131 (I-131-CLR1404) is a novel PLE molecule armed with I-131 resulting in targeted tumor cell radiotherapy which is being examined in relapsed or refractory WM through an open-label, Phase 2 trial, CLOVER-1 (NCT02952508). Methods: The primary objective of this study is to determine the efficacy and safety of CLR 131 in select B-cell malignancies. Eligibility criteria for WM pts include receipt of at least 2 prior treatment regimens unless ineligible to receive standard agents and have measurable disease: either IgM or extramedullary disease. CLR 131 is administered in up to 4 IV infusions (15-20 min) over 3 months. Adverse events (AEs) are graded by NCI-CTCAE v4.03; responses are assessed by the VIth WM Criteria for Response Assessment [Owen 2013]. Results: 6 pts with WM were enrolled in the study with data current as of 8 Jan 2021. The median age was 69 (range 54-81) with 4 females and 2 males who had a median of 2 prior regimens (range 1-5) and received a mean total body dose of 92.76 mCi CLR 131. 3 of 6 patients were MYD88 wild type (WT) of which 2 were dual WT (MYD88 WT & CXCR4 WT). The overall response rate (ORR) was 100% and the major response rate (MRR) was 83%, including 1 pt with a CR, 4 PR, and 1 MR. For those pts who were dual WT, the MRR was 100% and 1 pt who was MYD88 WT (CXCR4 is unknown) had a complete response. The median time to initial response was 48 days. Median duration of response (DOR) and treatment free remission (TFR) have not been reached; ongoing mean DOR is 335 days and mean TFR is 384 days. 100% of MYD88 WT patients have exceeded 6.5 months of follow up with average TFR of 18.1 months. The primary treatment emergent AEs in pts with WM included fatigue and cytopenias, in line with prior experience with CLR 131 in other B-cell malignancies. The most commonly observed cytopenias included Grade 3 or 4 thrombocytopenia (100%), neutropenia (83%), anaemia (66%) and decreased white blood cell count (33%). Of note, no cases of bleeding or febrile neutropenia were observed. Conclusions: Initial results for CLR 131 show efficacy across multiple WM patient genotypes including dual WT patients with durable DOR and TFR after 2 to 4 infusions. CLR 131 represents a novel and promising approach to the treatment of MYD88 WT patients who have a historical median time to progression of 1.3 years. These encouraging data led to the pivotal global CLOVER-WaM trial (N=50) in WM patients who have failed or had a suboptimal response to a Bruton Tyrosine Kinase inhibitor. CLOVER-WaM is currently enrolling. Clinical trial information: NCT02952508.

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A Phase II Study of Nilotinib, a Novel Tyrosine Kinase Inhibitor Administered to Patients with Hypereosiniphilic Syndrome (HES).

Blood ◽

10.1182/blood.v108.11.4912.4912 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4912-4912 ◽

Cited By ~ 1

Author(s):

Philipp le Coutre ◽

Andreas Hochhaus ◽

Dominik Heim ◽

Teresa Rafferty ◽

Aaron Weitzman ◽

...

Keyword(s):

Adverse Events ◽

Phase Ii ◽

Kinase Inhibitor ◽

Phase Ii Study ◽

Hypereosinophilic Syndrome ◽

Clinical Indication ◽

Clinical Activity ◽

Tolerability Profile ◽

Patient Death ◽

Chronic Eosinophilic Leukemia

Abstract Idiopathic hypereosinophilic syndrome (HES) is a rare myeloproliferative disorder characterized by sustained overproduction of eosinophils and organ involvement that can lead to chronic eosinophilic leukemia. HES is a clonal disorder characterized in some patients by constitutive activation of FIP1L1-PDGFRA. There is currently no approved therapy for HES. Nilotinib is a novel aminopyrimidine which potently inhibits Bcr-Abl, as well as the PDGF-R and c-Kit kinases. This Phase II study was designed to evaluate the safety and efficacy of nilotinib administered at an oral dose of 400 mg twice daily to patients with specific HES disease related criteria and with a clinical indication for treatment. Preliminary data are available for 11 patients. The median age is 63 (range 25–77) years. There were 10 males and 1 female. Extramedullary involvement was present in 6 (55%) patients at baseline. Treatment is ongoing for 4 (36%) patients and 7 (64%) have discontinued; 2 (18%) for adverse events; 3 (27%) for disease progression, and 1 (9%) for an administrative reason. There was one patient death due to neutropenic sepsis and endocarditis. Overall, 5 (45%) patients had investigator documented stable disease, and 1 (9%) patient a 51 year old male had a CR. Grade 3 or 4 adverse events included one patient each with rash, decreased hemoglobin, myalgia, arthralgia, pruritis, and diabetes mellitus. In summary, these data suggest that nilotinib has clinical activity and an acceptable safety and tolerability profile in patients with HES.

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