A Phase 1 Dose Escalation Study of Dual PI3K and DNA PK Inhibitor, BR101801 in Adult Patients with Advanced Hematologic Malignancies

Abstract Background: BR101801 not only blocks the signaling responsible for cell growth caused by PI3K, but also efficiently induces cell cycle arrest and apoptosis through inhibition of DNA-PK activation and stimulates decreasing stability of the oncogenic protein, c-Myc(AACR2020 abstract #655). This phase I study evaluated safety, tolerability, pharmacokinetics and preliminary activity of the BR101801 (PI3Kγ/δ and DNA PK inhibitor) in patients with advanced hematologic malignancies. Method: This is a Phase I, multi-center, open-label, first-in-human study. The Phase Ia (dose escalation) part of the study was designed to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of BR101801. BR101801 was administered orally once daily in 28-day cycles. The dose escalation part was initiated with a dose titration in the initial cohort, followed by a 3 + 3 design. Results: 11 patients were enrolled and have been treated at 4 dose levels: 50mg, 100mg, 200mg, 325mg and expanded 200mg through fifth cohort escalation. Pathological subtypes include 7 PTCL, 2 DLBCL, 1 MZBL and 1 composite CTCL/MF. 3 females and 8 males have been treated to date. Median age is 58 (range 30-71) and ECOG PS is in the range of 0-1. All patients had taken at least one prior chemotherapy. 10 of total patients have completed at least one cycle except 1 premature drop-out case due to disease progression. First interim analysis after completion of cycle 3 of the last patient of 200mg QD cohort had been conducted, which was to include 5 patients (1 DLBCL and 4 PTCLs). No DLT had been identified in Cohorts 1-3, and 2 patients discontinued the study treatment due to adverse event (G4 thrombocytopenia, not related to IP) and disease progression, respectively. The PK values from multiple dosing range of 50mg to 200mg cohort resulted in an approximate 2.92-fold and 4.97 fold increase in exposure based on Cmax and AUCtau, respectively. BR101801 PK profile showed that the exposure of concentration increased in a dose dependent manner and there was no accumulation observed in the dose range of 50mg to 200mg. 2 DLTs was observed at 325mg QD cohort. The dose was de-escalated to the previous lower dose level (200mg QD) and was expanded to 3 additional patients. The expansion cohort is ongoing at present. 2 of 11 patients had G3 skin reaction and 3 had G3 hepatotoxicites. All adverse effects were manageable and recovered to grade 0-1 upon BR1010801 discontinuation. Total 5 patients have been currently ongoing. For overall tumor response assessment, 4 SDs and 2 PRs have been obsereved. Summary/Conclusion: 200 mg QD of BR101801 was shown to provide target exposure for clinical efficacy with the tolerable and safe profiles. BR101801 was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory hematologic malignancies. The phase Ib/II study of BR101801 is warranted in relapsed/refractory NHL. This study is registered at clinicaltrials.gov identifier NCT04018248. Disclosures Kim: AstraZeneca-KHIDI: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GI CELL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boryung: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeyondBIO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca/MedImmune: Consultancy, Membership on an entity's Board of Directors or advisory committees. Curran: Servier pharmaceuticals and Amgen: Consultancy. Kim: Boryung pharmaceuticals: Current Employment.

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A Phase I/II Study of Escalating Doses of Thalidomide (Thal) in Conjunction with Bortezomib (Vel) and High Dose Melphalan (Mel) As A Conditioning Regimen for Autologous Peripheral Blood Stem Cell Transplantation (PBSCT) in Patients with Advanced Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v120.21.3104.3104 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3104-3104 ◽

Cited By ~ 1

Author(s):

Sung H Hong ◽

David S Siegel ◽

Michele L Donato ◽

David H. Vesole ◽

Andrew L Pecora ◽

...

Keyword(s):

Phase I ◽

Disease Progression ◽

Board Of Directors ◽

Phase Ii ◽

Dose Escalation ◽

Synergistic Effects ◽

Phase Iii ◽

High Dose ◽

Combination Regimen ◽

Advisory Committees

Abstract Abstract 3104 Thalidomide is an active agent in the treatment of MM and shows additive and/or synergistic effects when combined with various chemotherapeutics in pre-clinical and clinical models. We conducted a phase I/II study of Thal in combination with Vel and high dose Mel with PBSCT in patients (pts) with either disease progression or less than complete response after a prior PBSCT. Inclusion criteria included a diagnosis of MM and the availability of adequate PBSC. Exclusion criteria were dose-intense therapy within 56 days, uncontrolled infections, uncontrolled CNS metastases, known cardiac amyloid deposition, severe organ dysfunction, Karnofsky score <70%, or severe sensory neuropathy. Conditioning for PBSCT consisted of Vel 1.6 mg/m2 IVP on days -4 and -1 with Mel 200 mg/m2 on day -2. Thal was given on days -5 through -1. Thal was administered in a planned dose escalation steps of 600, 800 and 1000 mg (in cohorts of 3 pts) daily for 5 days. Dexamethasone (Dex) 10–20 mg was given prior to Vel and Mel. All pts received G-CSF every other day starting day +3 until engraftment. Serious adverse events (SAEs) were graded according to CTCAE ver 3. No dose limiting toxicities (≥ grade IV non-hematological SAE) occurred in the phase I portion of this study allowing full dose escalation with 9 pts enrolled. All pts experienced somnolence, more prominent at the 800 mg/day dose. Subsequently, Dex 40 mg was given with first dose of Thal at the 1000 mg level with improvement in sedation. In the phase II portion of the study, an additional 19 pts were treated with Thal 1000 mg daily. No regimen related mortality occurred in either phase I or phase II portion of the study. All SAEs except lethargy and dizziness occurred after PBSCT and were not attributed to Thal. All transplant-related SAEs resolved by day +28 after transplantation. All pts achieved prompt hematological recovery with the median time to ANC >500/uL 10 days (range, 8–14 days), ANC >1000/uL 10 days (range 9–14 days), and plt >20,000 12 days (range 9–25 days). 28 pts (median age, 56) were enrolled in the phase I and phase II portions of the study. 18 pts were treated for disease progression after prior autologous transplant (median lines of prior therapy =2; range, 1–5); only 22% of pts achieved ≥PR to the most recent therapy prior to PBSCT. 7 pts were enrolled after achieving <CR after prior PBSCT. Restaging evaluation was completed at 1, 2, and 3 months and every 3 months thereafter using the modified IMWG criteria. At three months after PBSCT (compared to immediate pre-transplant) the overall response rate ≥PR was 44% (1 CR, 4 VGPR, and 6 PR). An additional 10 pt achieved SD and 4 pts experienced disease progression. 4 subjects subsequently underwent allogeneic transplant and are not evaluable for long term response. The median event-free (EFS) was 7 months. The median overall survival (OS) has not yet been reached. The estimated EFS and OS probabilities at 2 years are 5% and 60%, respectably. Our results indicate that high-dose Thal can be safely added up to 1000 mg daily for 5 days to dose-intense Mel and Vel with acceptable toxicities. Confirmation of potential synergistic effects of this combination regimen will require an appropriately designed phase III study. Disclosures: Siegel: Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vesole:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Phase 1 Dose Escalation and Expansion Study to Determine Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the BET Inhibitor FT-1101 As a Single Agent in Patients with Relapsed or Refractory Hematologic Malignancies

Blood ◽

10.1182/blood-2019-124741 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3907-3907 ◽

Cited By ~ 2

Author(s):

Manish R. Patel ◽

Guillermo Garcia-Manero ◽

Ronald Paquette ◽

Shira Dinner ◽

William B. Donnellan ◽

...

Keyword(s):

Pleural Effusion ◽

Disease Progression ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Hematologic Malignancies ◽

Clinical Activity ◽

Advisory Committees ◽

Bet Inhibitor

Background: BET inhibitors have demonstrated therapeutic potential in hematologic malignancies; however low therapeutic margins have limited clinical development. FT-1101 (also known as CC-95775) is a BET bromodomain inhibitor of all 4 BET family members BRD4, BRD2, BRD3, and BRDT (Kd ≤20 nM) and shows additional activity towards several non-BET bromodomain proteins (including CECR2 and BRD9). In vitro, FT-1101 displayed potent anti-proliferative activity across a broad panel of human leukemia cell lines. In xenograft and syngeneic models, FT-1101 achieved superior tumor growth inhibition (including regressions) relative to JQ1, another BET inhibitor (Millan 2015). Methods: A Phase 1 study evaluated the safety, PK/PD, and clinical activity of FT-1101 in patients (pts) with relapsed/refractory (R/R) AML/MDS, or non-Hodgkin lymphoma (NHL) (NCT02543879). Oral FT-1101 (10 mg - 600 mg) was dosed once a week (QW), every other week (QOW), or monthly (QM) during dose escalation. Safety was assessed via treatment-emergent AEs (TEAEs) for all pts; efficacy (response) was assessed in evaluable pts by investigators. Pharmacodynamic biomarkers (CCR1 and HEXIM1 mRNA expression) were assessed in whole blood. Results: Between 17-Nov-2015 and 05-Mar-2019, a total of 84 AML/MDS pts and 10 NHL pts received FT-1101 in dose escalation with a median of 2 (range 1-13) treatment cycles and median exposure of 43 (1-401) days for AML/MDS and 51.5 (1-183) days for NHL pts. Most AML/MDS pts (n=80) received FT-1101 monotherapy; a small cohort (n=4) received FT-1101 200 mg QOW in combination with azacitidine. FT-1101 appeared to demonstrate dose-proportional PK (10-600 mg/dose) with a median Tmax of 4 (1-24) hrs and a mean T1/2 of 52 (18-123) hrs. Pharmacodynamic responses correlated with FT-1101 concentrations; preliminary analysis indicated that PD biomarker modulation (↓ CCR1 and ↑ HEXIM1) was seen with FT-1101 doses as low as 80 mg, with more robust modulation observed at FT-1101 doses >180 mg. The most common (>20%) TEAEs (all grades) were diarrhea (32%), fatigue (30%), dyspnea (29%), nausea (27%), anemia (24%), and platelet count decreased (21%) among AML/MDS pts and diarrhea (60%), nausea or pleural effusion (40% each), and cough, decreased appetite or dyspnea (30% each) among NHL pts. The most common (>10%) severe (≥ grade 3) TEAEs were anemia (21%), decreased platelets (19%), pneumonia (16%), sepsis (13%), febrile neutropenia (12%), and disease progression (11%) among AML/MDS pts and pleural effusion or disease progression (20% each) among NHL pts. AEs led to treatment discontinuation in 22 AML/MDS pts (26%) and 2 NHL pts (20%). Twenty AML/MDS pts (24%) and 2 NHL pts (20%) died due to AEs, all assessed as unrelated to study treatment. Disease progression was the most common fatal TEAE in AML/MDS and NHL pts (10% and 20%, respectively). The maximum tolerated dose (MTD) on the QOW schedule was 400 mg FT-1101; MTDs were not determined for other schedules. Among evaluable AML/MDS pts who received >180 mg FT-1101 monotherapy (n=30), one pt (3%) on the 400 mg QOW schedule achieved complete remission with incomplete hematologic recovery (CRi) and 19 pts (63%) achieved stable disease, including 2 pts receiving >7 cycles of treatment. Among evaluable NHL patients who received >180 mg FT-1101 monotherapy (n=3), one pt (33%) achieved stable disease. Conclusions: FT-1101, as monotherapy, shows acceptable safety, PK, and modest clinical activity in R/R AML/MDS and NHL pts. Intermittent (QOW) dosing within a tolerable range elicits PD activity (CCR1 suppression and HEXIM1 upregulation) consistent with preclinical observations indicating antitumor activity, and provides a rationale for testing FT-1101 in combination with standard therapies in AML/MDS and NHL. Disclosures Patel: Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Dinner:Agios: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy. Grunwald:Forma Therapeutics: Research Funding; Novartis: Research Funding; Celgene: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Daiichi Sankyo: Consultancy; Incyte: Consultancy, Research Funding; Medtronic: Equity Ownership; Cardinal Health: Consultancy; Merck: Consultancy; Genentech/Roche: Research Funding; Trovagene: Consultancy; Janssen: Research Funding. Ribadeneira:FORMA Therapeutics: Employment. Schroeder:FORMA Therapeutics: Employment. Brevard:FORMA Therapeutics: Employment. Wilson:FORMA Therapeutics: Employment. Sweeney:FORMA Therapeutics: Employment. Kelly:FORMA Therapeutics: Employment. Lancet:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy.

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Phase I-II Study of Clofarabine-Melphalan-Alemtuzumab (CMA) Conditioning for Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients with Advanced Hematologic Malignancies: Determination of MTD and Outcomes.

Blood ◽

10.1182/blood.v114.22.197.197 ◽

2009 ◽

Vol 114 (22) ◽

pp. 197-197 ◽

Cited By ~ 1

Author(s):

Koen van Besien ◽

Justin Kline ◽

Lucy A Godley ◽

Richard A. Larson ◽

Vu H. Nguyen ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Dose Level ◽

Phase Ii ◽

Renal Toxicity ◽

Phase Ii Study ◽

Hematologic Malignancies ◽

Advisory Committees ◽

Grade 3 ◽

One Year

Abstract Abstract 197 Supported by an unrestricted grant from Genzyme Corporation. Fludarabine (Flu) melphalan-alemtuzumab is a well tolerated, reduced intensity conditioning regimen for HCT. Clofarabine (Clo), a second generation nucleoside analog with excellent activity in acute leukemia, might enhance disease control over Flu. We report outcomes of a completed phase I and ongoing phase II study of CMA conditioning for allogeneic peripheral blood HCT. Tacrolimus was administered as GVHD prophylaxis. For the phase I cohort, one pt was enrolled per dose level, until the first DLT or until 2 had grade 3 toxicity. Dose level 1 consisted of: clo 10 mg/m2/day on d −7 to −3 and melphalan 100 mg/m2 on day −2. Clo was increased by 10 mg/m2/day per cohort until 40 mg/m2/day. Then, melphalan was increased by 20 mg/m2 until 140 mg/m2. Alemtuzumab was given at a fixed dose of 20 mg/day on d −7 to −3. Twelve pts were accrued in the phase I portion of whom three remain in remission at 26, 22 and 21 months. Forty pts, median age 53 (24–69), have been accrued in the phase II study of whom 16 had related and 24 unrelated donors. 20 had AML/MDS (6 refractory, 4 CR2, 9 CR1, 1 untreated MDS), 16 NHL (6 refractory, 9 chemosensitive relapse, 1 CR1) 2 CLL, 2 MPD. ASBMT risk score was high in 14, intermediate in 14, and low in 12. Performance score was 0 in 19, 1 in 17, 2 in 2, and not documented in 2 patients. The phase II dose was initiated at Clo 40 mg/m2/day x 5 days and melphalan 140 mg/m2. Twenty-four pts received this dose. Grade 3 renal toxicity occurred between day −7 and day +7 in 4 of 24 (17%) pts receiving this dose. The phase II dose was then reduced to Clo 30 mg/m2/day x 5 days and melphalan 140 mg/m2, and used to treat 16 pts. One pt with preexisting cardiomyopathy and refractory AML died during conditioning from cardiovascular failure. No grade 3 renal toxicity has been observed in this cohort and 3 pts had reversible grade 2 renal failure. Other toxicities included: gr 2–3 reversible ALT elevation between day −2 and day +5 in 8 pts; gr 2 reversible bilirubin elevation in 1 pt. No grade 3–4 hand foot syndrome or VOD occurred in this cohort. All evaluable pts engrafted. Twenty of 24 pts had full donor CD3 chimerism on day 30 and 2 had mixed donor chimerism. 11 pts had gr II aGVHD, and 3 had gr IIII/IV aGVHD. 7 have cGVHD.With a median follow-up of 313 days (19–607), 24 of 40 pts (60%) in the phase II portion of the study remain in remission. Eight have relapsed, 4 of whom have died. Eight others have died of treatment-related causes (7 after Clo 40 and 1 after Clo 30). Estimated one year survival is 72% (95%CI, 56–88) and PFS is 63% (45–81%). Neither dose of Clo (40 vs 30), donor type (MUD vs related), age (< 50 vs >50) affected outcomes. One year PFS was 56% (28–84) for NHL and 68% (46–90) for AML/MDS (P=NS). One year PFS was 43% (15–71%) for ASBMT high risk pts vs 70% (50–90%) for ASBMT low/intermediate risk pts (P=0.01; Figure 1). Conclusions: Clofarabine - melphalan - alemtuzumab conditioning induces durable remissions in a substantial fraction of patients with advanced hematologic malignancies. Clo 30/Mel 140 has an excellent safety profile. Disclosures: Off Label Use: clofarabine for transplant conditioning. Kline:Genzyme corporation: Membership on an entity's Board of Directors or advisory committees. Odenike:Genzyme corporation: Membership on an entity's Board of Directors or advisory committees. Stock:Genzyme: Research Funding.

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Clinical Pharmacokinetics of Apto-253 Support Its Use As a Novel Agent for the Treatment of Relapsed or Refractory Hematologic Malignancies

Blood ◽

10.1182/blood.v126.23.4934.4934 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4934-4934 ◽

Cited By ~ 1

Author(s):

William G. Rice ◽

Jeff Lightfoot ◽

Hongying Zhang ◽

Tiffany Cheng ◽

Avanish Vellanki ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Solid Tumors ◽

Fold Increase ◽

Hematologic Malignancies ◽

Mrna Levels ◽

Advisory Committees ◽

Clinical Pharmacokinetics ◽

Equity Ownership ◽

Hydroxylated Metabolite

Abstract APTO-253 is a novel anticancer small molecule currently in a multicenter open-label, Phase I dose escalation study in patients with relapsed or refractory hematologic malignancies. APTO-253 has potent cytotoxic activity against leukemia, lymphoma and myeloma cell lines IC50s of 6.9 - 305 nM. APTO-253 produces significant tumor growth inhibition in the KG-1, THP-1 and Kasumi-1 xenograft models of human acute myeloid leukemia (AML). The anticancer activity of APTO-253 is mediated through induction of Krüppel-like factor 4 (KLF4), a tumor suppressor that is epigenetically silenced in many solid tumors and hematologic cancers. KLF4 expression is often downregulated in AML due to repressive binding of CDX2 to the KLF4 promoter. Increased levels of CDX2 are found in the majority of patients with AML and ALL, as well as in 40% of MDS patients, whereas CDX2 is not expressed in normal hematopoietic cells. Treatment of cultured AML cells with APTO-253 reverses the KLF4 silencing, resulting in induction of p21 and cell death by apoptosis. KG-1 AML cells treated with APTO-253 showed time- and concentration-dependent induction of KLF4 and a concentration-dependent increase in p21 mRNA levels following induction of KLF4. APTO-253 treatment of KG-1 cells for 24 h induced a 14-fold increase in KLF4 mRNA and 16-fold increase in p21 mRNA over basal levels. Following washout of APTO-253, the level of KLF4 mRNA decayed to approximately 50% of maximum induction level over a 24 h period. The potential for APTO-253 as a therapeutic option in AML was further supported by safety and pharmacokinetics data from an earlier Phase I trial of APTO-253 in patients with advanced or metastatic solid tumors during which APTO-253 was administered at doses of 20 - 387 mg/m2 using a dosing schedule of days 1 and 2, and 15 and 16 of a 28 day cycle. APTO-253 showed a dose-dependent increase in Cmax and AUC, and as the dose was escalated from 80 to 176 mg/m2 the Cmax ranged from 1,800 - 4,960 nM on day 1 and 1,600 - 6,100 nM on day 2. These results suggest that exposure levels from these doses of APTO-253 should be sufficient for single agent activity in patients with AML and other hematologic malignancies. APTO-253 demonstrated a favorable safety profile when tested against 5 major cytochrome P450 enzymes (1A2, 2C19, 2C9, 2D6 and 3A4), against a panel of proteins and receptors, and in the hERG tail current density assay. Metabolic profiling of APTO-253 at 50 μM in human liver microsomes showed no glutathione or glucuronide conjugation and only a minor hydroxylated metabolite. Finally, 1 μM APTO-253 did not inhibit kinases in a safety panel (40 kinases) or in a broad oncology panel (98 kinases), demonstrating that APTO-253 activity is not driven by kinase inhibition. Taken together, our results demonstrate that APTO-253 has substantial potential for the treatment of AML and other hematologic malignancies and is of particular interest due to its ability to modulate the expression of the KLF4 master transcription factor that plays a central role in restraining the growth of leukemic cells. Disclosures Howell: Aptose Biosciences: Consultancy, Equity Ownership; Angstrom: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abeoda: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; InhibRx: Equity Ownership.

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Phase I/II Study of Escalating Doses of Thalidomide in Conjunction with Bortezomib and High Dose Melphalan As a Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-114832 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2154-2154

Author(s):

Noa Biran ◽

Shijia Zhang ◽

Scott D. Rowley ◽

David H. Vesole ◽

Michele L. Donato ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Conditioning Regimen ◽

High Dose ◽

Advisory Committees ◽

Common Grade ◽

Grade 3 ◽

High Dose Melphalan

Abstract Background: A regimen of escalating doses of thalidomide, in combination with bortezomib and high dose melphalan (Mel/Vel/Thal) was evaluated as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients (pts) with multiple myeloma (MM) in a phase I/II study. Methods: Patients received Mel/Vel/Thal as a second of tandem ASCT if they achieved <CR to their first ASCT (tandem), or as conditioning for a salvage ASCT (salvage). Exclusion criteria were dose-intense therapy within 56 days, uncontrolled infections, severe organ dysfunction, Karnofsky score <70%, or painful grade 2 or greater peripheral neuropathy. Conditioning consisted of Vel 1.6 mg/m2 intravenously on days -4 and -1 with Mel 200 mg/m2 on day -2. Thal was given on days -5 through -1 and was administered in a planned step-wise dose escalation of 600, 800 and 1000 mg (in cohorts of 3 pts). Dexamethasone (Dex) 10-20 mg was given prior to Vel and Mel. All pts received G-CSF every other day starting day +3 until engraftment. Serious adverse events (SAEs) were graded according to CTCAE version 3. Results: Twenty-nine pts were enrolled: 9 in the phase 1 dose-escalation phase and an additional 20 pts in phase 2. In the phase I portion, all pts experienced somnolence, with grade 3 occurring in 1 pt at the 800 mg/day dose. Subsequently, Dex 40 mg was given with first dose of Thal at the 1000 mg level with decreased severity of somnolence. No dose limiting toxicities defined as ≥ grade 4 non-hematological SAEs occurred in the phase I portion, allowing full dose escalation with 9 pts enrolled. The maximum tolerated dose for Thal was not reached and the 1000 mg dose was chosen for the phase 2 dose expansion. No regimen related mortality occurred in either phase I or phase II portion of the study. All SAEs except lethargy and dizziness occurred after ASCT and were not attributed to Thal. The most common grade 1 and 2 non-hematologic toxicities included nausea (65.5%), mucositis (51.7%), diarrhea (48.3%), somnolence (48.3%), lethargy (27.6%), and vomiting (17.2%). The most common grade 3 non-hematologic adverse events (AEs) were neutropenic fever (58.6%), mucositis (6.9%), and somnolence (13.8%), which increased risk of falls. SAEs included somnolence (13.8%), tumor lysis syndrome (3.4%), and engraftment syndrome (3.4%). All transplant-related SAEs resolved by day +28 after ASCT. All pts achieved prompt hematological recovery with the median time to ANC >500/uL 10 days (range, 8-14 days), and platelet >20,000 12 days (range 9-26 days). All pts received at least one ASCT prior to enrolling on the study. Seventeen pts (59%) had interim salvage chemotherapy between their upfront and Mel/Vel/Thal ASCT (i.e. received a salvage ASCT), with median time from first to salvage ASCT 29 months. The remaining 12 (41%) went directly from an upfront ASCT Mel-based ASCT to the Mel/Vel/Thal ASCT (tandem ASCT) within 6 months of the first ASCT. Twenty-seven (93%) were Durie-Salmon stage III, and 13 (44%) had >2 prior lines of therapy. Of those who had Mel/Vel/Thal as a salvage ASCT, 70% had ≥3 prior lines of therapy. The overall response rate (ORR) was 69% with 38% complete remission. ORR for Mel/Vel/Thal compared to upfront Mel ASCT was 69% versus 62% with 11 patients achieving CR with Mel/Vel/Thal compared to 5 patients with Mel alone (Figure 1). Ten of 27 evaluable patients (37%) had an upgrade in response in the Mel/Vel/Thal salvage ASCT compared to their upfront ASCT: 2 pts (7%) went from PD to PR, 1 (4%) from SD to CR, 1 (4%) from PR to VGPR; 3 (11%) from PR to CR and 2 (7%) from VGPR to CR. Median PFS and OS were 9.3 and 65.4 months, respectively, with a median follow-up of 17.8 months. Of those who underwent tandem Mel followed by Mel/Vel/Thal ASCT the median PFS was 14.9 months with a median OS not yet reached at time of analysis. For the 17 patients who received a salvage Mel/Vel/Thal ASCT, median PFS from their upfront ASCT was 11.9 months, compared to 9.1 months with the salvage Mel/Vel/Thal ASCT. Conclusions: High-dose Thal up to 1000 mg daily for 5 days can be safely combined with Vel and dose-intense Mel as an ASCT conditioning regimen with acceptable toxicities. Confirmation of potential synergistic effects of this combination regimen will require an appropriately designed phase III study. Figure 1 Figure 1. Disclosures Biran: BMS: Research Funding; Merck: Research Funding; Takeda: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Siegel:Novartis: Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients with Relapsed or Refractory AML or CMML

Blood ◽

10.1182/blood-2019-121954 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3855-3855

Author(s):

Marina Ciomei ◽

Lucia Zanetta ◽

Federico Lussana ◽

Erika Ravelli ◽

Francesco Fiorentini ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Single Agent ◽

Dose Titration ◽

Advisory Committees ◽

Secondary Resistance ◽

Support Research ◽

Refractory Aml

Background: NMS-03592088 is a novel, potent inhibitor of the FLT3, CSF1R and KIT receptor tyrosine kinases (KD < 1 nM for all three targets). The compound demonstrated high preclinical efficacy following oral administration in all tested target-dependent tumor models, including those harboring kinase domain secondary resistance mutations, such us the FLT3 residue 691 gatekeeper mutation and the KIT residue 670 and exon 17 mutations. In a FLT3-ITD model of disseminated AML, efficacy observed following single agent treatment with NMS-03592088 was further significantly increased when administered in combination with cytarabine, with excellent tolerability. In preclinical studies conducted in non-human primates, a dose-related increase of circulating CSF1 levels was observed in association with the administration of NMS-03592088, consistent with in vivo inhibition of CSF1R by the compound, thus providing the opportunity for the use of CSF1 levels as a potential pharmacodynamic biomarker of CSF1R modulation in the clinical setting. All three targets of NMS-03592088 are relevant in different settings of hematologic malignancies and solid tumors. In particular, FLT3 mutations occur in approximately 30% of acute myeloid leukemia patients (AML), and are associated with a poor prognosis; KIT mutations are reported in patients with the core-binding factor (CBF) subtype of AML and the CSF1 and/or CSF1R genes are frequently expressed in AML blasts. Recent experimental evidence suggests a potential therapeutic rationale for CSF1R blockade in AML, possibly due to interference with microenvironmental support [Edwards DK et al, Blood, 2019, 133: 588]. Furthermore, chronic myelomonocytic leukemia (CMML) blasts express high levels of CSF1R and NMS-03592088 was able to effectively inhibit their proliferation, concomitant with the suppression of intracellular CSF1R dependent signalling. A clinical trial exploring safety, tolerability and efficacy of NMS-03592088 in patients with AML and CMML is therefore warranted. Trial design: This first-in-human study (EudraCT Number: 2018-002793-47) is designed as an open-label multicenter Phase I/II trial including patients with relapsed or refractory AML or CMML who have exhausted standard treatment options, or for whom standard therapy is considered unsuitable. The study is designed to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics and to explore the preliminary anticancer activity of NMS-03592088 administered orally as single agent once daily for 21 consecutive days, followed by a 7-day break within a 28 day cycle. The study includes an initial conventional phase I part with an accelerated dose titration design in subsequent cohorts of 3+3 patients aimed at defining the maximal tolerated dose (MTD) and the recommended phase 2 dose (RP2D), followed by a limited dose expansion to confirm the RP2D. Once the RP2D is confirmed, a single-stage exploratory Phase II part will start comprising two parallel cohorts, one cohort will consist of AML FLT3 mutated patients and one of patients with CMML. Patients previously treated with FLT3 inhibitors are allowed to participate. The primary endpoint of the Phase II portion of the study is Overall Response Rate. Efficacy will be assessed according to standard criteria [Döhner H et al, Blood 2017, 129: 424; Savona MR et al., Blood, 2015, 125: 1857]. Exploratory endpoints are included to evaluate the potential effects of treatment with NMS-03592088 on circulating levels of CSF1 in plasma, the potential correlation of cellular CSF1R expression levels with clinical outcome in both AML and CMML, and the mutational status of a panel of leukemia-related genes, not limited to FLT3. The Phase I part started in Italy in March, 2019 and is currently ongoing. Disclosures Ciomei: NMS: Employment. Zanetta:Clioss: Employment. Fiorentini:Accelera: Employment. Bosotti:NMS: Employment. Ardini:NMS: Employment. Lombardi Borgia:NMS: Employment. Pulci:Accelera: Employment. Gatto:Clioss: Employment. Di Sanzo:Clioss: Employment. Colajori:Clioss: Consultancy. Davite:Clioss: Employment. Galvani:NMS: Employment. Gan:NMS: Employment. Rossi:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria; Daiichi-Sankyo: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees. Rambaldi:Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Isacchi:NMS: Employment.

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Blockade of IL-15 Utilizing Bnz-1, a Selective γ-Chain Inhibiting Peptide, Is Safe and Has Clinical Activity in Patients with T-Cell Large Granular Lymphocytic Leukemia (T-LGLL): Results of a Phase I/II Multi-Center Clinical Trial

Blood ◽

10.1182/blood-2019-129291 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2835-2835 ◽

Cited By ~ 1

Author(s):

Jonathan E. Brammer ◽

Lubomir Sokol ◽

Yutaka Tagaya ◽

Kerry Rogers ◽

Anjali Mishra ◽

...

Keyword(s):

Clinical Trial ◽

T Cell ◽

Phase I ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Weekly Dose ◽

Advisory Committees ◽

Large Granular Lymphocytic Leukemia

T-cell large granular lymphocytic leukemia (T-LGLL) is an incurable, and likely under-diagnosed leukemia characterized by abnormal clonal proliferation of CD8+ memory T-cells. The clonal outgrowth of T-LGLL cells can lead to the development of profound neutropenia and anemia which results in frequent infections, transfusion dependence, and impairment in quality of life and lifespan. There have been few prospective clinical trials in this disease, and no drugs have been FDA approved for its treatment. The primary driver of leukemogenesis in T-LGLL is known to be interleukin-15 (IL-15), a gamma-chain cytokine that induces proliferation of T-LGLL cells. BNZ-1 is a novel pegylated peptide antagonist that inhibits IL-15 by binding to the common γ-chain receptor for cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Studies utilizing BNZ-1 in vitro on T-LGLL cell lines, and ex vivo on clinical patient samples demonstrated significant inhibition of downstream signaling and increased LGLL cell apoptosis (Wang et al., Leukemia 2018). Given these results, we conducted a phase I/II dose escalation study to evaluate the safety, maximum tolerated dose (MTD), and preliminary efficacy of BNZ-1 in T-LGLL (NCT03239393). Patients with T-LGLL were eligible if they had one or more of the following: absolute neutrophil count (ANC) <500 cells/m3, neutropenia with recurrent infections, or symptomatic or transfusion-dependent anemia. Diagnosis of T-LGLL required: >400/mm3 CD3+CD57+ cells or >650 mm3 CD8+ cells, with a clonal T-cell receptor rearrangement. No prior therapy within 30 days or 5 half-lives was permitted. MTD was evaluated using a standard 3+3 design; with a dose escalation strategy using four doses of BNZ-1: 0.5 mg/kg, 1 mg/kg, 2 mg/kg, and 4 mg/kg. BNZ-1 was administered by infusion on Days 1, 8, 15, and 22 of a 4-week cycle. Patients then had the option to enter the 3-month extension period, at the same weekly dose. Efficacy was determined utilizing criteria from the ECOG5998 study in T-LGLL. CR was defined as complete normalization of blood counts. Partial response (PR) in neutropenic patients was determined by 4 weeks or greater response with ANC >500 cells/mm3 if >/=50% improvement from baseline. For transfusion-dependent anemia patients, a >/=50% decrease in monthly transfusions for at least 2 months was required for a PR. For patients with symptomatic anemia, improvement in hemoglobin >/=1 g/dL with improvement in symptoms constituted a PR. Patients with a response were permitted to remain on a long-term extension (LTE). Eighteen patients, at 3 US centers were enrolled on study including: 3 patients at 0.5 mg/kg, 4 at 1 mg/kg, 5 at 2 mg/kg, and 6 at 4 mg/kg. 10 patients were enrolled for neutropenia, 4 for transfusion dependent anemia, 2 for symptomatic anemia, and 2 with anemia and neutropenia. 15 patients (83%) completed all 16 weeks of treatment, 2 patients declined to enter the extension phase, and one patient on the 2 mg/kg dosage was taken off study at 4 weeks due to neutropenia <100 thought secondary to T-LGLL. One patient developed grade 2 hyperbilirubinemia, which was thought possibly due to study drug though was grade 1 at baseline.The MTD was not reached. Four patients attained a PR: 3 patients with transfusion-dependent anemia became transfusion independent, while one patient with neutropenia had significant resolution of her neutropenia (Table). These three patients remain on the LTE, though one patient is under observation. Correlative studies demonstrated apoptosis of T-LGLL cells on flow cytometry utilizing CD3 T-cell gating within 24 hours of the first dosage of BNZ-1 (a representative example is shown in the Figure), confirming in patients that inhibition of IL-15 induces apoptosis of T-LGLL cells. In this Phase I/II clinical trial, IL-15 blockade utilizing BNZ-1 demonstrated increased apoptosis in patients with T-LGLL, with early evidence of clinical response, particularly amongst patients with transfusion-dependent anemia. Remarkably, these patients remained transfusion-independent while on BNZ-1. The MTD was not reached in this cohort of patients, and there were minimal AEs associated with BNZ-1. Further analysis of responding patients is underway to determine the most effective approach utilizing BNZ-1 in this rare disease. Table Disclosures Brammer: Celgene: Research Funding; Seatlle Genetics: Honoraria, Speakers Bureau. Sokol:EUSA: Consultancy. Tagaya:Bioniz: Membership on an entity's Board of Directors or advisory committees; Bioniz: Research Funding. Rogers:AbbVie: Research Funding; Acerta Pharma: Consultancy; Genentech: Research Funding; Janssen: Research Funding. Waldmann:Bioniz: Membership on an entity's Board of Directors or advisory committees. Azimi:Bioniz: Employment. Frohna:Bioniz: Employment. Ratnayake:Bioniz: Employment. Loughran:Bioniz: Membership on an entity's Board of Directors or advisory committees; Keystone Nano: Membership on an entity's Board of Directors or advisory committees.

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Venetoclax Monotherapy for Relapsed/Refractory Multiple Myeloma: Safety and Efficacy Results from a Phase I Study

Blood ◽

10.1182/blood.v128.22.488.488 ◽

2016 ◽

Vol 128 (22) ◽

pp. 488-488 ◽

Cited By ~ 18

Author(s):

Shaji Kumar ◽

Ravi Vij ◽

Jonathan L. Kaufman ◽

Joseph Mikhael ◽

Thierry Facon ◽

...

Keyword(s):

Multiple Myeloma ◽

Disease Progression ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Objective Response ◽

White Blood Cells ◽

Cell Transplant ◽

Weekly Dose ◽

Advisory Committees

Abstract Background: Venetoclax (VEN) is a potent, selective, orally available small-molecule BCL-2 inhibitor that induces cell death in multiple myeloma (MM) cell lines and primary samples, particularly those with t(11;14), which mostly have a favorable high BCL-2, low BCL-XL, and low MCL-1 profile. Methods: In this Phase 1, open-label study, patients (pts) with relapsed/refractory (R/R) MM received VEN monotherapy. Objectives of the study were to assess safety, pharmacokinetics, maximum tolerated dose, recommended phase 2 dose, and efficacy (objective response rate [ORR], time to progression [TTP], and duration of response [DoR]) of VEN. After a 2-week lead in period with weekly dose escalation, VEN was given daily at final doses of 300, 600, 900, or 1200mg in dose escalation cohorts and 1200mg in the safety expansion. Pts who progressed during VEN monotherapy could receive VEN plus dexamethasone and continue in the study. Results: As of 01July2016, 66 pts were enrolled in the study (30 in dose escalation cohorts and 36 in safety expansion). Median age was 63 years and 39 (62%) pts were ISS stage II/III. The median number of prior therapies was 5 (range: 1-15), and 62 (94%) pts had received bortezomib (46 [70%] refractory), 62 (94%) received lenalidomide (51 [77%] refractory), and 50 (76%) had prior autologous stem cell transplant. Thirty (46%) pts had t(11;14) MM. Median time on VEN monotherapy for all pts was 2.5 months (.2-23); 17 (26%) elected to receive VEN and dexamethasone combination after disease progression for a median of 1.4 months (.1-11). Fifty-one (77%) pts discontinued the study for the following primary reasons: 39 related to disease progression, 5 due to AEs/toxicity, 2 withdrew consent, 1 was lost to follow up, and 4 for other reasons not specified. Common adverse events (AEs) in ≥20% of pts were nausea (48%), diarrhea (36%), neutropenia (32%), thrombocytopenia (32%), fatigue (27%), anemia (23%), back pain (21%), and vomiting (21%). Grade 3/4 AEs in ≥10% of pts were thrombocytopenia (26%), neutropenia (20%), lymphopenia (15%), anemia (14%), and decreased white blood cells (12%). Serious AEs in ≥2 pts were pneumonia (n=5), sepsis (3), pain, pyrexia, cough, and hypotension (2 each). Two pts experienced dose-limiting toxicities at 600mg of abdominal pain and nausea. Eight deaths were reported: 6 due to disease progression, 1 due to lung disorder, and 1 due to brain hemorrhage following injury; neither were considered by the investigator as related to VEN. Steady state VEN exposures were approximately dose proportional at all doses but 900mg. As of 20July2016, ORR for all pts on VEN monotherapy was 21% (14/66) and 10 (15%) achieved very good partial response (VGPR) or better (2 stringent complete response [sCR], 2 CR, 6 VGPR) (Figure); median DoR and TTP was 9.7 and 2.6 months, respectively. Most objective responses (12/14 [86%]) were reported in the subset of pts with t(11;14) MM. In this group, ORR was 40% (12/30) and 27% (8/30) achieved a response of ≥VGPR; median DoR for pts with t(11;14) was 9.7 months (95% CI: 6.3, -). Pts who achieved at least minimal response in the t(11;14) group (14/30) had a median of 4 prior therapies and were mostly refractory to bortezomib, lenalidomide, or double refractory (71% [10/14] each). For two pts with response in the non-t(11;14)/undetermined group, 1 had a translocation of chromosome 14 with an unidentified partner, and the other had no cytogenetics data available. DoR was 9.5 and 7.2 months in these pts and both are still ongoing. Median TTP for pts with or without/undetermined t(11;14) was 6.6 and 1.9 months, respectively. The median best percent change in primary M protein for pts with t(11;14) (n=23) was -53% vs +11% in the non-t(11;14)/undetermined group (n=23). Additional biomarker subgroup analyses (n=32) showed that efficacy was primarily observed in pts with myeloma cells expressing a favorable BCL-2 family expression profile (high BCL-2, low BCL-XL, low MCL-1) by immunohistochemistry, which was significantly enriched in the t(11;14) population. Indeed, although high BCL-2 expression was observed in a majority of bone marrow core biopsy samples (88%), the t(11;14) subgroup was enriched (81% vs 25%) for tumors expressing high BCL-2, low BCL-XL, and low MCL-1. Conclusions: VEN monotherapy has an acceptable safety profile and clear anti-myeloma activity in pts with R/R MM, primarily with t(11;14) having a high BCL-2, low BCL-XL and low MCL-1 expression levels. Figure Figure. Disclosures Kumar: Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kesios: Consultancy; BMS: Consultancy. Kaufman:Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy; Incyte: Consultancy. Mikhael:Abbvie: Research Funding; Celgene: Research Funding; Onyx: Research Funding; Sanofi: Research Funding. Facon:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol: Consultancy; Millenium/Takeda: Consultancy; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Karyopharm: Consultancy. Benboubker:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Alzate:AbbVie: Employment. Ross:AbbVie: Employment, Equity Ownership. Dunbar:AbbVie Inc.: Employment, Other: may own stock. Xu:AbbVie: Employment. Agarwal:AbbVie: Employment. Leverson:AbbVie: Employment, Other: Shareholder in AbbVie. Maciag:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Touzeau:AbbVie: Research Funding.

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Weekly Carfilzomib, Cyclophosphamide and Dexamethasone (wCCd) in Newly Diagnosed Multiple Myeloma Patients: A Phase I- II Study

Blood ◽

10.1182/blood.v124.21.175.175 ◽

2014 ◽

Vol 124 (21) ◽

pp. 175-175 ◽

Cited By ~ 4

Author(s):

Antonio Palumbo ◽

Davide Rossi ◽

Sara Bringhen ◽

Alessandra Larocca ◽

Fabiana Gentilini ◽

...

Keyword(s):

Partial Response ◽

Phase I ◽

Board Of Directors ◽

Dose Level ◽

Dose Escalation ◽

Research Funding ◽

Maximum Tolerated Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3

Abstract Background Carfilzomib is a novel second generation proteasome-inhibitor with significant anti MM activity and favorable toxicity profile, including very limited neurotoxicity and neutropenia. This Phase I/II study was designed to determine the maximum tolerated dose (MTD) of once weekly carfilzomib combined with cyclophosphamide-dexamethasone (wCCd) and to assess safety and efficacy of this combination in elderly patients with newly diagnosed MM. Here we report the first findings from the Phase I dose-escalation and expansion portions. Enrolment in the phase II portion is ongoing. Methods In the Phase I, the standard 3+3 dose-escalation scheme was adopted, with Carfilzomib as the only escalating agent starting at 45 mg/m2 (level 0), maximal planned dose 70 mg/m2 (level 2), and 36 mg/m2, if needed (level -1), given IV on days 1, 8, 15 in 28-day cycles. Oral cyclophosphamide was administered at 300 mg/m2 on days 1, 8, 15 and oral dexamethasone at 40 mg on days 1, 8, 15, 22 for all dose levels. Dose escalation of Carfilzomib was based on dose-limiting toxicities (DLTs) occurring in cycle 1. After completion of 9 cycles, patients receive 28-day maintenance cycles with Carfilzomib (days 1, 8, 15) at the maximum tolerated dose (MTD) defined by the Phase I study until disease progression or intolerance. The objectives were to determine the MTD and assess activity and safety. Results As of June 15, 2014, 28 newly diagnosed MM patients were enrolled. Median age was 74 years, 29% of patients were older than 75 years, 36% had ISS stage III, 24% had unfavorable FISH profile [t(4;14) or t (14;16) or del17p]. Twelve patients were enrolled in the Phase I portion of the study. At dose level 0 (Carfilzomib 45 mg/m2) no DLT was reported; at dose level 1 (Carfilzomib 56 mg/m2), 1 of 6 patients experienced DLT, consisting of grade 3 creatinine increase; at dose level 2 (Carfilzomib 70 mg/m2) no DLT occurred. The MTD of weekly Carfilzomib was thus established as 70 mg/m2. Toxicity and response data are available for 25 patients, who have completed at least the first cycle; 3 patients are currently receiving their first cycle of treatment. Grade 3-4 drug-related adverse events occurred in less than 15% of patients and included neutropenia (12%, 3 patients), anemia (12%, 3 patients), acute pulmonary edema (8%, 2 patients), pulmonary embolism (4%, 1 patient), creatinine increase (4%, 1 patient), nausea (4%, 1 patient), and fatigue (4%, 1 patient). No peripheral neuropathy was observed. Overall, the wCCd regimen was well tolerated, 3 patients (12%) required Carfilzomib dose reduction (grade 3 creatinine increase, grade 3 transaminase increase and grade 2 fever) and 3 patients (12%) required drug discontinuation due to adverse events (2 acute pulmonary edemas and 1 creatinine increase). Patients received a median of 5 cycles (range 1-9). After 4 induction cycles, 83% of patients achieved at least partial response, 39% at least very good partial response, and 22% complete response. Responses improved over time, as shown in table 1. During the study, only 2 patients progressed and 1 patient died, due to acute pulmonary edema considered probably related to treatment. Conclusions This is the first prospective study evaluating once weekly carfilzomib in treatment-naïve MM. wCCd therapy appears safe and effective in newly diagnosed MM patients. Responses became deeper with subsequent cycles and toxicities were manageable. The response rate observed with weekly carfilzomib compares favorably with similar studies with standard twice weekly carfilzomib infusion. Updated results will be presented at the meeting. Table 1 2nd cycle 4th cycle 6th cycle Complete Response 5% 22% 27% At least Very Good Partial Response 9% 39% 63% At least Partial Response 73% 83% 91% Disclosures Palumbo: Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Off Label Use: Use off-label of Carfilzomib (proteasome inhibitor).. Bringhen:Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria; Onyx: Consultancy. Larocca:Janssen Cilag: Honoraria; Celgene: Honoraria. Cavallo:Onyx: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gaidano:Onyx: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Millenium: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

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Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics from a Phase I Study of PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood-2019-121805 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1869-1869 ◽

Cited By ~ 13

Author(s):

Noopur S. Raje ◽

Andrzej Jakubowiak ◽

Cristina Gasparetto ◽

Robert F. Cornell ◽

Heike I. Krupka ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Phase I Study ◽

Employment Equity ◽

Advisory Committees ◽

Best Response ◽

Equity Ownership ◽

Dose Levels

Introduction: PF-06863135 (PF-3135) is a bispecific, humanized, monoclonal antibody (mAb) consisting of BCMA- and CD3-targeting arms paired on an IgG2a backbone by hinge-mutation technology. PF-3135 binds BCMA+ myeloma cells and CD3+ T cells with affinities of 20 pM and ~40 nM, respectively (Panowski et al. Blood 2016). We report here findings from the dose-escalation portion of an ongoing, multi-center, open-label, phase I study (NCT03269136) of PF-3135 in patients with RRMM. Methods: Adult patients (≥18 years of age) with RRMM, previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 mAb, received escalating, intravenous (IV) doses of PF-3135, once weekly. Prior BCMA-targeted bispecific T-cell engager or chimeric antigen receptor T-cell (CART) treatment was allowed by protocol. Patients had measurable disease per the International Myeloma Working Group (IMWG) updated criteria 2014. A modified toxicity probability interval method (mTPI), targeting a dose-limiting toxicity (DLT) rate of 25% (equivalence interval ± 5%) was used for dose escalation. The primary study objectives are to assess PF-3135 safety and tolerability, to determine the maximum tolerated dose (MTD) and select the recommended phase II dose (RP2D). Secondary objectives include evaluation of anti-myeloma activity, pharmacokinetics (PK), and immunogenicity of PF-3135. Results: As of April 9, 2019, 17 patients had received once weekly, non-continuous, IV infusion of PF-3135 in 6 dose-escalation groups. The majority were men (71%). The median age was 61 yrs (range, 47-82 yrs) and median disease duration since onset was 7 yrs (range, 1.1-13.3 yrs). Ten (59%) patients had ≥1 chromosomal abnormality and 5 (29%) had a normal karyotype (status not known for 2 [12%] patients). The median number of prior anti-myeloma therapies was 11; 5 (29%) patients had received prior BCMA-targeted therapy. Eight (47%) patients had relapsed MM and 8 (47%) had refractory disease (recurrence type not known for 1 [6%] patient). Ten (59%) patients experienced treatment-related (TR) AEs of any grade. Most TRAEs were grade 1-2, including cytokine release syndrome (CRS, 24%), thrombocytopenia (24%), anemia (18%), and pyrexia (18%). Three (18%) patients had grade 3 TRAEs (increased alanine aminotransferase/aspartate aminotransferase, leukocytopenia, neutropenia, and lymphopenia). One patient treated at the highest dose level, who had received prior BCMA CART therapy, developed treatment-related febrile neutropenia, a DLT, which may have been related to CRS and borderline/low neutrophil count at baseline. None of the patients had grade 4-5 TRAEs or discontinued treatment due to a TRAE. The median duration of treatment was 4 (range, 2-12) actual dosing days. Sixteen of the 17 patients were evaluable for response. At the time of data cut-off, one (6%) patient had a minimal response and 6 (35%) patients had stable disease (SD) across dose levels, as best response by investigator IMWG assessment; 9 (53%) patients experienced disease progression. The clinical benefit rate (defined as best response ≥SD) was 41% (95% CI: 18.4%, 67.1%). Conclusions: Treatment with IV PF-3135 was well tolerated at the dose levels evaluated. The observed CRS events were moderate and dose-dependent. Additional dose cohorts are accruing. The latest clinical, biomarker, and PK data will be presented for this ongoing study. Disclosures Raje: Medscape: Honoraria; Research to Practice: Honoraria; Takeda: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AstraZeneca: Research Funding. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Cornell:KaryoPharm: Consultancy; Takeda: Consultancy. Krupka:Pfizer: Employment, Equity Ownership. Navarro:Pfizer: Employment, Equity Ownership. Forgie:Pfizer: Employment, Equity Ownership. Udata:Pfizer: Employment, Equity Ownership. Basu:Pfizer: Employment, Equity Ownership. Chou:Pfizer: Employment, Equity Ownership. Leung:Pfizer: Employment, Equity Ownership. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Serametrix Inc.: Patents & Royalties; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Juno: Consultancy, Honoraria; GenMab: Consultancy, Honoraria; Janssen: Research Funding. OffLabel Disclosure: PF-06863135, investigational agent

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