scholarly journals Biological and Clinical Impact of JAK2/mTOR Blockade in Gvhd Prevention: Preclinical and Phase I Trial Results

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 48-49
Author(s):  
Joseph Pidala ◽  
Kelly Walton ◽  
Hany Elmariah ◽  
Jongphil Kim ◽  
Asmita Mishra ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Acute Gvhd ◽  
Advisory Committees ◽  
Mtor Inhibition ◽  
Level 1 ◽  
Level 2

Background: Distinct from broadly acting graft-versus-host disease (GVHD) prophylaxis, JAK2 inhibition suppresses alloreactive T cells, while sparing regulatory T cells (Tregs) and graft-versus-leukemia (GVL). Early IL-6 activity via JAK2 and phosphorylated STAT3 in CD4+ T cells is associated with acute GVHD onset. In mice, we show combined JAK2/mTOR blockade synergistically prevents xenogeneic GVHD. In this first-in-human phase I/II GVHD prevention trial we combine pacritinib, a JAK2 inhibitor, with sirolimus to concurrently reduce T-cell costimulation via mTOR and IL-6 activity. With phase I complete, we demonstrate that dual JAK2/mTOR inhibition is safe, suppresses pathogenic Th1 and Th17 cells, spares Tregs and key GVL effector cells, and exhibits preliminary activity in preventing GVHD. The primary aim of phase I was to identify the lowest biologically active dose of pacritinib (defined as < 35% of CD4+ pSTAT3+ T cells at day +21) that is safe when combined with sirolimus-based immune suppression. The preliminary activity of JAK2/mTOR inhibition in GVHD prevention was also investigated. Materials and Methods: This single-arm phase I/II trial (NCT02891603) tested the safety of pacritinib when administered with sirolimus plus low-dose tacrolimus (PAC/SIR/TAC) after allogeneic hematopoietic cell transplantation (alloHCT). A 3+3 dose escalation design was followed, including dose level 1 (PAC 100mg daily), level 2 (PAC 100mg twice daily), and level 3 (PAC 200mg twice daily). Clinical safety, pharmacodynamic assessments, and pharmacokinetic (PK) studies were followed during the study. Acute GVHD was scored through day +100. Patient characteristics are described in Table 1 (n=12). Allowed donor types were HLA-A, -B, -C, and -DRB1 matched-related or unrelated donors. Adequate vital organ function and Karnofsky performance status (KPS ≥ 80%) were required. Results: Dose level 2, PAC 100mg twice a day, was the lowest biologically active and safe dose, and thus the recommended phase II dose. Blood samples acquired at day +21 showed that PAC 100mg twice a day reduced the mean frequency and geometric MFI of CD4+ pSTAT3+ T cells (Figure 1A, B). Consistent with suppressed pSTAT3, PAC 100mg twice a day decreased pathogenic Th1 and Th17 cells (Figure 1C, D). pSTAT5 is critical for Tregs and effectors of GVL. PAC 100mg twice a day favored STAT5 phosphorylation in CD4+ T cells, preserved Tregs and increased the ratio of Tregs to pathogenic T helper cells, and supported CD3+ T cell and NK cell effectors (Figure 1E-J). Patients treated on dose level 2 of PAC exhibited a robust increase in Th2 cells at day +21 (29.5% v 4.87% level 1 or 4.5% baseline, P<0.001 ANOVA). Additionally, neutrophil and platelet engraftment occurred without delay (Figure 1K, L). A single dose limiting toxicity was observed in dose level I only, and consisted of angioedema possibly related to PAC. CMV reactivation or disease were not observed among patients treated at dose level 2, with only a single case of CMV reactivation among dose level 1 (8 of 12 recipients were CMV seropositive). A single patient treated on dose level 2 developed grade 4 acute GVHD and died, after prematurely discontinuing TAC for acute kidney injury and electively stopping PAC. A patient died of relapsed disease in dose level 1. To test the efficacy of dual JAK2/mTOR inhibition in vivo, NSG mice were transplanted with human peripheral blood mononuclear cells (PBMCs) and treated with either vehicle, PAC, STAT3 inhibitor S3I-201, SIR, PAC/SIR, or S3I/SIR. The combination of JAK2 or downstream STAT3 inhibition plus SIR significantly reduced xenogeneic GVHD in mice (Figure 1M) and maintained donor anti-tumor activity by CD8+ T cells (data not shown). Further, dual JAK2 or STAT3 inhibition with mTOR blockade significantly increased the induction of Tregs in mice transplanted with Treg-depleted human PBMCs (62.3% PAC/SIR or 74% S3I/SIR v 29.9-38% with vehicle or inhibitors alone, P<0.01 ANOVA). Conclusions: We demonstrate that PAC/SIR/TAC (RP2D: PAC 100mg twice a day) is safe and effectively reduces IL-6 signal transduction, pathogenic Th1 and Th17 cells, and preserves Tregs and effectors necessary for GVL and antiviral immunity. Preliminarily, adding pacritinib limits acute GVHD, preserves donor CMV immunity, and permits timely engraftment. The efficacy of PAC/SIR/TAC will be tested in our ongoing phase II GVHD prevention trial. Disclosures Pidala: Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees. Nishihori:Karyopharm: Other: Research support to institution; Novartis: Other: Research support to institution. Lawrence:Patent Pending: Patents & Royalties: Dr. Lawrence has a patent WO2014070859A1: Stat3 dimerization inhibitors. . Lawrence:Patent Pending: Patents & Royalties: Dr. Lawrence has a patent WO2014070859A1: Stat3 dimerization inhibitors. . Sebti:Patent Pending: Patents & Royalties: Dr. Sebti has a patent WO2014070859A1: Stat3 dimerization inhibitors. . Betts:Patent Pending: Patents & Royalties: Dr. Betts has a pending patent WO2017058950A1: Methods of treating transplant rejection. This includes the use of JAK inhibitors. Neither he nor his institution have received payment related to claims described in the patent.. OffLabel Disclosure: Pacritinib and its use in GVHD prevention as part of a phase I trial

scholarly journals Phase I Trial of Systemic Administration of Vesicular Stomatitis Virus Genetically Engineered to Express NIS and Human Interferon, in Patients with Relapsed or Refractory Multiple Myeloma (MM), Acute Myeloid Leukemia (AML), and T-Cell Neoplasms (TCL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3268-3268
Author(s):  
Martha Q. Lacy ◽  
Kah-Whye Peng ◽  
Stephen J. Russell ◽  
Amylou C. Dueck ◽  
Mrinal M. Patnaik ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Tumor Burden ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Background: We previously reported successful treatment of myeloma with an oncolytic virus, MMV-NIS. Preexisting immunity against measles made use of that virus unsatisfactory. The Indiana strain of Vesicular Stomatitis Viruses (VSV) are being developed as anticancer drugs for the treatment of a variety of malignancies. To ensure tumor selective replication and spread, we designed the VSV to encode interferon beta. Expression of IFNβ also serves as a STING agonist to activate host immunity against the cancer. The sodium iodide symporter (NIS) is inserted as a reporter gene into the viral genome to enable noninvasive monitoring of viral spread using PET/CT imaging. We report a Phase I clinical trial of intravenous administration of VSV-IFNβ-NIS for relapsed hematological malignancies including MM, AML, and TCL. Methods: Arm A consisted of patients with low tumor burden. Arm B included patients with high tumor burden. Both arms consisted of a classical 3+3 phase I trial, starting at 5x10^9 TCID50 (dose level 1) through 5x10^11 TCID50 (dose level 4), given as a single IV dose. In order to obviate potential toxicity from high interferon levels, Arm B received ruxolitinib 15 mg twice daily for 10 days beginning on day -1. The primary objective was determining the maximum tolerated dose (MTD) of VSV-IFNβ-NIS alone and in combination with ruxolitinib; secondary objectives include estimating the safety profile and preliminary efficacy. Correlative objectives include monitoring the pharmacodynamics of viral replication through SPECT/CT imaging with NIS gene, viremia, virus shedding, changes in the immune profile of peripheral blood leukocytes, and immunohistochemistry for immune cell infiltrates in tumors. Adverse events (AEs) are reported herein based on CTCAE v4 with the exception of cytokine release syndrome (CRS) which is based on Lee (Blood 2014; 124(2):188-195) criteria. Results: To date, 10 patients have received IV VSV-IFNβ-NIS; 8 in Arm A and 2 in Arm B. In Arm A, 3 patients were treated at dose level 1, 3 at dose level 2 and 2 at dose level 3. At dose level 1, there were three grade 3 hematologic AEs (neutropenia [1], lymphopenia [2]), and no grade 3+ non-hematologic AEs. At dose level 2, there were two grade 3 hematologic AEs (anemia [1], lymphopenia [1]), and two grade 3 non-hematologic AEs (nausea [1], dehydration [1]). A grade 2 CRS by Lee criteria was also observed. At dose level 3, 2 patients have been enrolled and data are maturing for DLT evaluation. In Arm B (VSV + rux), 2 patients have been enrolled and data are maturing for dose limiting toxicity (DLT) evaluation. Other grade 1 and 2 toxicities have included fever, hypertension, headache, electrolyte abnormalities, nausea, vomiting, transient elevation of liver function tests and creatinine. All grade 1 and 2 toxicities resolved within 72 hours. Among the 6 patients evaluable for response, there was one partial remission (TCL patient treated at dose level 2), and 5 with progressive disease. Multiple cytokines increased at 4h post infusion of virus, but most returned to baseline levels by 24h.Viremia was detectable in all patients at the end of infusion, and to varying levels at 30 mins, 1, 2, 4, 24, 48h or 72 hours post virus infusion. No persistent viremia was observed. No infectious virus was recovered in buccal swabs or urine and neutralizing anti-VSV antibodies were present by day 29. Extensive immune phenotyping and ELIspot assays for shared antigens are ongoing. Conclusion: In the lowest dose levels tested to date, VSV-IFNβ-NIS has not led to any observed dose limiting toxicity. Dose escalation is ongoing and updated results will be reported. Disclosures Lacy: Celgene: Research Funding. Peng:Vyriad: Equity Ownership. Russell:Vyriad: Equity Ownership. Dueck:Bayer: Employment; Phytogine: Employment; Pfizer: Honoraria. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:spectrum: Consultancy, Honoraria; Physicians Education Resource: Consultancy; Ionis: Honoraria; janssen: Consultancy; Medscape: Consultancy; celgene: Consultancy; Apellis: Consultancy; Prothena: Honoraria; Amgen: Consultancy; annexon: Consultancy; Abbvie: Consultancy; Research to Practice: Consultancy; Teva: Consultancy; Alnylam: Honoraria. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Al-Kali:Novartis: Research Funding. Naik:Vyriad: Equity Ownership. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals A Pilot Study of CPX-351 (Vyxeos ©) for Transplant Eligible, Higher Risk Patients with Myelodysplastic Syndrome

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 540-540
Author(s):  
Meagan A. Jacoby ◽  
David A. Sallman ◽  
Bart L. Scott ◽  
Megan Haney ◽  
Fei Wan ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Induction Dose ◽  
Level 1 ◽  
Level 2 ◽  
Very High

Abstract Introduction: CPX-351 (Vyxeos ©; daunorubicin and cytarabine liposome for injection) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar drug ratio that is FDA approved for treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Secondary AML is clinically and biologically similar to MDS, sharing many of the same genetic mutations. We hypothesize that CPX-351 therapy may result in deeper responses than traditional therapy with hypomethylating agents, with acceptable tolerability, and translate into better outcomes in the MDS population. This is a multicenter, dose-escalation and safety expansion study (NCT03572764) to investigate induction and consolidation therapy with CPX-351 in a transplant eligible, higher risk MDS population. Methods: Two dose levels were investigated in the dose-escalation portion. Induction Dose Level 1: (daunorubicin 29 mg/m 2 and 65 mg/m 2 cytarabine) liposome on days 1, 3, 5; and Induction Dose Level 2: (daunorubicin 44 mg/m 2 and 100 mg/m 2 cytarabine) liposome on Days 1, 3, 5. The primary objectives were to evaluate safety and to determine the dose-limiting toxicities (DLTs) and recommended Phase 2 dose (RP2D). DLTs were assessed during the induction period (up to day 56 to evaluate for prolonged myelosuppression). Additionally, a dose expansion (for up to 20 treated patients) was performed at the RP2D. After induction, patients could receive up to two cycles of consolidation per dose level: Dose Level 1, (daunorubicin 14.3 mg/m 2 and 32 mg/m 2 cytarabine) liposome on Days 1 and 3; or Dose Level 2 (daunorubicin 29 mg/m 2 and 65 mg/m 2 cytarabine) liposome on Days 1 and 3. After induction, the patient could proceed to alloHCT at any time at the discretion of the treating physician. Key eligibility criteria included MDS patients who were naïve to hypomethylating agents, aged 18-70 years, an IPSS-R score > 3 (Intermediate, High or Very High Risk), ≥ 5% bone marrow myeloblasts, and suitable candidates for cytotoxic induction therapy and allogeneic hematopoietic cell transplant (alloHCT). Key secondary endpoints were day 30 and 60 post-induction mortality, the proportion of patients proceeding to alloHCT, and response assessments per IWG 2006 criteria. Results: As of abstract submission, 19 patients have been treated and dose escalation is complete. The dose escalation portion included 12 patients (Dose Level 1, n=6; Dose Level 2, n=6), and the safety expansion to date includes 7 patients treated at Dose Level 2. The median age was 64 years (range, 18-68), 67% were female, and the IPSS-R risk categories were as follows: intermediate (n=1, 5%), high (n=10, 53%) and very high (n=8, 42%). There were no DLTs in either Dose Level 1 or Dose Level 2, and Dose Level 2 was selected for safety expansion. Treatment-emergent adverse events (TEAEs) were evaluated in the 18 patients who had completed induction (Table). The most common TEAEs were hematologic, as expected. The most common non-hematologic TEAEs were febrile neutropenia (n=13, 72.2%), hypertension (n=9, 50%), and sepsis (n=5, 27.8%). SAEs included febrile neutropenia (n=5), sepsis (n=2), lower GI hemorrhage (n=2, two instances in the same patient), atrial fibrillation (n=1), pneumonitis (n=1), and catheter related infection (n=1). To date, the 30 and 60 day mortality is 0% and 5% (n=1), respectively, with the 1 death unrelated to therapy and due to progression of disease to AML. Of the 19 patients, 13 have received alloHCT with 4 still potentially alloHCT candidates. Of response evaluable pts (n=18, 1 pt pending response evaluation at data cutoff), the overall response rate was 78% with best overall responses of CR (n=4), mCR (n=10), stable disease (n=2), progressive disease (n=2) and pending (n=1). Of the 10 patients with mCR, 3 also had hematologic improvements. Conclusions: CPX-351 (daunorubicin 44 mg/m 2 and 100 mg/m 2 cytarabine) liposome on Days 1, 3, 5, has demonstrated a tolerable safety and promising efficacy profile when used in a transplant eligible, higher risk MDS population, warranting further study. Updated safety and efficacy outcomes will be presented at the meeting. Figure 1 Figure 1. Disclosures Jacoby: Abbvie: Research Funding; Jazz: Research Funding. Sallman: Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Incyte: Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees. Scott: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Komrokji: AbbVie: Consultancy; Acceleron: Consultancy; Geron: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Uy: AbbVie: Consultancy; Macrogenics: Research Funding; Agios: Consultancy; GlaxoSmithKline: Consultancy; Novartis: Consultancy; Genentech: Consultancy; Astellas: Honoraria, Speakers Bureau; Jazz: Consultancy. OffLabel Disclosure: CPX-351 (Vyxeos©; daunorubicin and cytarabine liposome for injection) is FDA approved for treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes

Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy Induces High Response Rates in Agressive Chronic Lymphocytic Leukemia (CLL) and Richter's Syndrome (RS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3443-3443 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
William Wierda ◽  
William Plunkett ◽  
Susan O'Brien ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rates ◽  
Off Label ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 3443 Poster Board III-331 Introduction The first Phase I-II clinical trial of oxaliplatin, fluradabine, cytarabine (Ara-C), and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate and decrease myelosuppression, the dose of oxaliplatin was increased to 30mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods In a Phase I-II study of OFAR2, patients were treated with oxaliplatin 30mg/m2, D1-4; fludarabine 30mg/m2, Ara-C 0.5g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg, D6. Fludarabine and Ara-C were given on D2-3 (dose level 1) D2-4 (dose level 2) or D2-5 (dose level 3); courses were repeated every 4 weeks. Patients received prophylaxis for tumor lysis, DNA viruses, and PCP. A “3+3” design was used and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results Ninety-one patients (CLL, 67; RS, 24) have been treated to date: Phase I, 12 patients (by dose level: 1, n=3; 2, n=6; and 3, n=3). DLTs were noted in 2 of 3 patients on dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1); thus, dose level 2 was the MTD. Seventy-nine patients (relapsed CLL, 58; RS, 19) have been treated in the Phase II portion of the study. Patient characteristics were as follows: age > 60 years, 65%; 17p deletion, 38%; 11q deletion, 13%; 13q deletion, 16%; trisomy 12, 21%; no findings, 12%; unmutated IgVH, 80%; ZAP70-positive, 75%; and CD38 ≥30%, 58%. Response in patients treated in the Phase II recommended dose is shown in Table (evaluable, 67). The overall response rates in patients with 17p and 11q deletions were 48% and 55%, respectively. The median survival duration was 21 months (CLL, 21 months; RS, 9.5 months). At 18 months, the survival rates in patients with 17p and 11q deletions were 66% and 76%, respectively. Twelve patients underwent stem cell transplantation after OFAR2 (as post-remission therapy, n=10; as salvage, n=2). Overall, 196 cycles were administered. Grade 3-4 neutropenia, thrombocytopenia, and anemia were noted in 63%, 72%, and 39% of patients and in 57%, 70%, and 25% of cycles and Grade 3-4 infections in 19% of patients. Conclusion Preliminary results demonstrated that OFAR2 induced response in 40% of patients with RS and 63% of patients with relapsed/refractory CLL. OFAR2 had antileukemic activity in patients with 17p deletion. Clinical outcomes appeared to be superior to those of OFAR1 in refractory CLL, whereas results of OFAR1 appeared to be superior to those of OFAR2 in RS. Accrual is ongoing. Disclosures Tsimberidou: ASCO: ASCO Career Development Award; Sanofi: Research Funding. Off Label Use: Oxaliplatin is used off-label. Wierda:Genentech: Honoraria; Bayer, Sanofi-Aventis, Abbott, GSK: Research Funding; GSK, Trubion, Ligand, Genentech, Medimmune, Abbot: Consultancy; Celgene: Speakers Bureau. Plunkett:Sanofi-Aventis: Research Funding. O'Brien:Genentech: Research Funding; Sanofi: Consultancy. Kipps:NCI: Grant P01CA-81534.

Carfilzomib, Lenalidomide, and Dexamethasone In Newly Diagnosed Multiple Myeloma: Initial Results of Phase I/II MMRC Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 862-862 ◽  
Author(s):  
Andrzej J Jakubowiak ◽  
Dominik Dytfeld ◽  
Sundar Jagannath ◽  
David H. Vesole ◽  
Tara B. Anderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Level 3 ◽  
Equity Ownership ◽  
Level 1 ◽  
Level 2

Abstract Abstract 862 Background: Carfilzomib (Cfz) is a novel, irreversible proteasome inhibitor that has demonstrated promising single-agent activity and favorable toxicity profile, including very low rates of peripheral neuropathy and neutropenia in relapsed/refractory multiple myeloma (MM). Combining Cfz with Lenalidomide (Revlimid®, Len), and Dexamethasone (Dex) into CRd shows an additive anti-MM effect in preclinical studies and lack of overlapping toxicity allowing for the use of these agents at full doses and for extended duration of time in relapsed/refractory MM (Niesvizky et al, ASH, 2009). This Phase I/II study was designed to determine the maximum tolerated dose (MTD) of CRd and to assess safety and evaluate efficacy of this combination in newly diagnosed MM. Methods: In Phase I, dose escalation follows the TITE-CRM algorithm, with Cfz as the only escalating agent starting at 20 mg/m2 (level 1), maximal planned dose 27 mg/m2 (level 2), and 15 mg/m2, if needed (level -1), given IV on days 1, 2, 8, 9, 15, 16 in 28-day cycles. Len is used at 25 mg PO (days 1–21), and Dex at 40/20 mg PO weekly (cycles 1–4/5-8) for all dose levels. Based on toxicity assessment, the study was amended to add dose level 3 with Cfz at 36 mg/m2 and the number of pts in the Phase I was increased to 35. A total of 36 pts are planned to be treated at the MTD in Phase I/II. Pts who achieve ≥ PR can proceed to stem cell collection (SCC) and autologous stem cell transplant (ASCT) after ≥ 4 cycles, although per protocol design, ASCT candidates are offered to continue CRd treatment after SCC. After completion of 8 cycles, pts receive 28-day maintenance cycles with Cfz (days 1, 2 15, 16), Len days 1–21, and Dex weekly at the doses tolerated at the end of 8 cycles. Responses are assessed by IMWG criteria with the addition of nCR. Results: The study has enrolled 24 pts to date, 4 pts at level 1 (Cfz 20), 14 at level 2 (Cfz 27) and at 6 at level 3 (Cfz 36). Toxicity data are available for 21 pts, of which 19 have completed at least the first cycle required for DLT assessment; 2 pts were removed during the first cycle for events unrelated to study therapy (1 at level 1 and 1 at level 2), and 3 are currently within their first cycle of treatment. There was a single DLT event at dose level 2 (non-febrile neutropenia requiring dose reduction of Len per protocol) and the MTD has not been reached. Hematologic toxicities were reversible and included Grade (G) 3/4 neutropenia in 3 pts, G3/4 thrombocytopenia in 3, and G3 anemia in 2. There have been additional G3 non-hematologic AEs including 1 case of DVT while on ASA prophylaxis, 1 fatigue, 1 mood alteration, and 5 glucose elevations; the last 2 AEs were related to Dex. There was no emergence of peripheral neuropathy (PN), even after prolonged treatment, except in 2 pts who developed G1 sensory PN. Twenty-three pts continue on treatment, most (20 pts) without need for any dose modifications. After a median of 4 (range 1–8) months of treatment, preliminary response rates by IMWG in 19 evaluable pts who completed at least 1 cycle are: 100% ≥ PR, 63% ≥ VGPR, 37% CR/nCR, including 3 pts with sCR. Responses were rapid with 17 of 19 pts achieving PR after 1 cycle and improving responses with continuing therapy in all pts. To date, 7 pts proceeded to SCC using growth factors only, with a median 6.3 × 106 CD34+ cells/kg collected (range 4.1–8.2), after a median of 4 cycles of CRd (range 4–8); all resumed CRd treatment after SCC. After a median of 4 months of follow-up, none of evaluable pts progressed and all are alive. Conclusion: CRd is well tolerated and highly active in newly diagnosed MM with ≥ PR of 100%, including 63% ≥VGPR and 37% CR/nCR. Accrual is ongoing, with updated toxicity and efficacy data to be presented at the meeting. The results of this study represent the first report of treatment of frontline myeloma with Cfz to date, and provide additional support to recently initiated Phase 3 trial of CRd vs. Rd in relapsed MM. Disclosures: Jakubowiak: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Centocor OrthoBiotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide for newly diagnosed multiple myeloma. Jagannath:Millennium: Honoraria; OrthoBiotech (Canada): Honoraria; Celgene: Honoraria; Merck: Honoraria; Onyx Pharmaceuticals: Honoraria; Proteolix, Inc: Honoraria; Imedex: Speakers Bureau; Medicom World Wide: Speakers Bureau; Optum Health Education: Speakers Bureau; PER Group: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Anderson:Millennium: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Stockerl-Goldstein:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Barrickman:Celgene: Employment, Equity Ownership. Kauffman:Onyx Pharmaceuticals: Employment, Equity Ownership. Vij:Proteolix: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Phase 1 Results of Anti-PD-Ligand 1 (Durvalumab) & Lenalidomide in Patients with Cutaneous T Cell Lymphoma and Correlation with Programmed Death Ligand 1 Expression and Gene Expression Profile

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4024-4024
Author(s):  
Christiane Querfeld ◽  
Xiwei Wu ◽  
Tracy Stiller ◽  
Joycelynne Palmer ◽  
James F Sanchez ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Board Of Directors ◽  
Gene Expression Profile ◽  
Dose Level ◽  
Expression Profile ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 2 ◽  
Advisory Committees

Background: T cells in CTCL are functionally exhausted and are characterized by the expression of immune inhibitory molecules such as PD1 and PD-L1 (Cancer Immunol Res 6; 2018). These findings justify the evaluation of immune checkpoint inhibition to reverse T cell exhaustion in CTCL. We initiated a phase 1/2 clinical trial of lenalidomide and durvalumab to determine the safety and efficacy of this regimen. Durvalumab is a human monoclonal antibody with high affinity and selectivity for PD-L1, targeting exhausted T cells and distinct cells within their environment. Lenalidomide, an oral immunomodulatory drug (IMiD) and analog of thalidomide, has previously shown activity in CTCL (Blood 123; 2014). Durvalumab may restore an anti-tumor immune response, and the combination of durvalumab and lenalidomide may enhance immune checkpoint blockade-induced immune responses. Associations between immune checkpoints, gene expression profile and the clinical efficacy of durvalumab/lenalidomide combination were evaluated. The primary objectives were to determine the recommended phase 2 dose of lenalidomide in combination with durvalumab and safety with primary endpoint of toxicity (using CTCAE 4.03). Secondary end points included objective response rate (ORR) and median duration. Relationships between gene expression profile (GEP), PD-L1 expression, and antitumor activity were exploratory end points. Methods: A Phase 1 portion (NCT03011814) is ongoing to evaluate the safety and tolerability of the durvalumab and lenalidomide combination. Pts are enrolled in sequential cohorts to receive durvalumab (fixed dose at 1500 mg) and dose escalation of lenalidomide (dose level 1 = 10 mg for all cycles; dose level 2 = 10 mg for cycle 1, 15 mg for all subsequent cycles; dose level 3 =10 mg for cycle 1, 15 mg for cycle 2, and 20 mg for all subsequent cycles) to characterize safety, efficacy and antitumor activity. Serial skin samples were collected to assess the impact on the tumor microenvironment and anti-tumor activity. Results: Ten pts. were evaluable for toxicities. Nine patients were evaluable for response with three patients at each dose level. 8 males/2 females, age 29-59 y, with refractory/advanced CTCL, clinical stages IB (1), IIA (3), IIB (4), IIIA (1), and aggressive epidermotropic CD8+ CTCL (1) and a median of prior systemic treatments of 3 (range, 2-4) have been enrolled. Median follow up time was 12 (range, 3-24+) months. No serious AEs or DLTs were observed during the DLT evaluation period (cycles 1-3). The most frequently reported AEs were fatigue (n=7), skin pain (n=4), chills (n=3), anemia (n=3), and leukopenia (4). One grade 3 maculopapular rash (possibly due to lenalidomide) was observed, all other treatment-related AEs were grade 1/2 in severity. Median cycles of treatment were 7 (range, 3-20+) months. Median duration of response was 4 (range, 1- 21+) months. Six pts achieved PR, while 3 pts maintained stable disease. Three pts remain on treatment. Expression panels of several checkpoints (PD1, PD-L1 & ICOS) (Cycle1 Day1 vs Cycle 2 Day15) were analyzed. Detectable levels of PD-L1 but low levels of ICOS are observed in responding pts vs. high PD-L1 and ICOS levels in non-responders. GEP highlights downregulation of TNF-alpha signaling via NFkB, IFN-gamma, and PI3-AKT-mTOR signaling pathways among other pathways. Conclusions: Durvalumab/lenalidomide has significant clinical activity in refractory/advanced CTCL, which will be formally evaluated in the Phase 2 portion. Responses were durable and ongoing, and treatment was well tolerated. Dose escalation is up to lenalidomide 20 mg daily. Our preliminary results from pts on trial demonstrated that immune signatures on skin biopsies at baseline may be predictive of response to checkpoint blockade and yield insights into mechanisms of therapeutic resistance. Disclosures Querfeld: Bioniz: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Soligenix: Other: Investigator; Celgene: Other: Investigator, Research Funding; City of Hope Cancer Center and Beckman Research Institute: Employment; Medivir: Consultancy; Trillium: Consultancy, Other: Investigator, Research Funding; miRagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Kyowa: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Eisai: Other: Investigator; Elorac: Other: Investigator, Research Funding; Helsinn: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator. Palmer:Gilead Sciences: Consultancy. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy.

A Phase I Safety Study of Enzastaurin Plus Bortezomib in the Treatment of Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1870-1870
Author(s):  
Irene M Ghobrial ◽  
Nikhil C Munshi ◽  
Brianna N Harris ◽  
Zheng Yuan ◽  
Nichole M Porter ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Progressive Disease ◽  
Loading Dose ◽  
Advisory Committees ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3

Abstract Abstract 1870 Poster Board I-895 Background: Enzastaurin is an oral serine/threonine kinase inhibitor that targets the PKC and PI3K/AKT pathways. Enzastaurin has demonstrated activity in preclinical models of multiple myeloma (MM), and clinical studies suggest activity and a favorable safety profile in a variety of hematological cancers. Enzastaurin has also demonstrated in-vitro synergy with bortezomib. Objectives: This phase I, open-label, multicenter, dose-escalation study was initiated to identify the recommended doses of enzastaurin and bortezomib in combination for phase II studies in patients (pts) with previously treated MM. Secondary objectives included evaluations of safety and response. Patients and Methods: A conventional dose-escalation scheme was applied. In dose level 1, pts received enzastaurin as a loading dose of 500 mg (250 mg po BID) on day 1 followed by daily doses of 125 mg po BID plus bortezomib 1.0 mg/m2 IV on days 8, 11, 15, and 18 in cycle 1 and days 1, 4, 8, and 11 thereafter. In dose level 2, pts received the same enzastaurin dose but a higher bortezomib dose (1.3 mg/m2). In dose level 3, pts received enzastaurin as a loading dose of 1125 mg (375 mg po TID) on day 1 followed by daily doses of 250 mg po BID plus 1.3 mg/m2 bortezomib. All treated pts were evaluated for response using the International Uniform Response Criteria (IURC; Durie et al. 2006) and European Group for Blood and Bone Marrow Transplantation (EBMT) criteria (Blade et al. 1998). All adverse events (AEs) were graded according to Common Toxicity Criteria for Adverse Events (CTCAE) v3.0. Results: A total of 23 pts, 4 in dose level 1, 3 in dose level 2, and 16 in dose level 3, were enrolled in the study, which is now closed to enrollment. There were 8 women and 15 men, with a median age of 62 years (range, 37–78 years); 91% of the pts had an ECOG performance status of 1 or 0, and the median number of prior systemic therapies was 3 (range, 2–12), with 17 pts previously treated with bortezomib. The median number of cycles completed was 4 (range, 1–20). No dose-limiting toxicities (DLTs) were observed; thus, dose level 3 was the recommended phase II dose. The combination was well tolerated with few grade 3/4 AEs. CTCAE drug-related grade 3/4 laboratory toxicities included: thrombocytopenia in 5 (22%) pts, anemia in 2 (9%) pts, increased creatinine in 1 (4%) pt, and hyponatremia in 1 (4%) pt. Drug-related grade 3/4 non-laboratory toxicities included: sensory neuropathy, prolonged QTc interval, and renal/genitourinary in 1 (4%) pt each. Serious drug-related AEs were increased serum creatinine and renal tubular necrosis in 1 (4%) pt and thrombocytopenia in 1 (4%) pt. The thrombocytopenia was not considered a DLT as the baseline platelet count was low secondary to MM. Five (22%) pts were discontinued from the study due to drug-related toxicities: renal tubular necrosis (also a serious AE) in 1 (4%) pt, peripheral neuropathy in 2 (9%) pts, neuralgia in 1 (4%) pt, and pain in extremity in 1 (4%) pt. There were no deaths on therapy; 1 pt died within 30 days of treatment due to progressive disease. Of the 23 enrolled pts, objective responses based on IURC criteria included 1 (4%) pt with a very good partial response (dose level 1), 2 (9%) pts with a partial response (in dose levels 2 and 3), 9 (39%) pts with stable disease, and 3 (13%) pts with progressive disease; 2 pts had no post-baseline response assessment, and 6 pts had unconfirmed stable disease or progressive disease. Two (9%) pts had a minimal response based on EBMT criteria. Activity was seen in pts regardless of prior exposure to bortezomib. Conclusions: The recommended phase II dose in patients with MM is enzastaurin 250 mg po BID with a loading dose of 1125 mg (375 mg po TID) on day 1 plus 1.3 mg/m2 bortezomib on days 1, 4, 8, and 11 (days 8, 11, 15, and 18 in cycle 1 only). The combination was generally well tolerated, and responses were observed. Disclosures: Ghobrial: Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Celgene: Honoraria, Speakers Bureau. Munshi:Millenium: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yuan:Eli Lilly and Company: Employment. Schlossman:Millenium: Speakers Bureau; Celgene: Speakers Bureau. Laubach:Novartis: Consultancy. Anderson:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millenium: Consultancy, Honoraria, Research Funding. Lin:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Richardson:Millenium: 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; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gentium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

A Multicenter, Open Label Study of Oral Lenalidomide and Prednisone (RP) Followed by Oral Lenalidomide Melphalan and Prednisone (MPR) and Oral Lenalidomide Maintenance In Newly Diagnosed Elderly Multiple Myeloma Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1940-1940 ◽  
Author(s):  
Antonio Palumbo ◽  
Patrizia Falco ◽  
Giulia Benevolo ◽  
Davide Rossi ◽  
Angelo Michele Carella ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Autologous Transplantation ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 1940 The combination of Melphalan-Prednisone-Lenalidomide (MPR) has shown promising results in elderly newly diagnosed myeloma patients. In the transplant setting, low-dose chemotherapy (induction) precedes high-dose chemotherapy (autologous transplantation consolidation). This approach reduces tumor mass, with few side effects, before achieving the maximum cyto-reduction with autologous transplantation. The same approach has been designed for the elderly patients. Accordingly induction with lenalidomide plus corticosteroids precedes consolidation with MPR. A two-stage phase II clinical trial was planned to evaluate the safety and efficacy of Lenalidomide-Prednisone (RP) as induction, followed by Melphalan-Prednisone-Lenalidomide (MPR) as consolidation and Lenalidomide as maintenance in elderly myeloma patients. Unfit patients with newly diagnosed symptomatic myeloma older than 65 years were enrolled. No exclusion criteria were included in the protocol, to avoid the selection of fit elderly subjects only. Patients with low blood count, abnormal performance status, hepatic, renal, cardiac or pulmonary functions were enrolled. Patients received 4 RP courses (Lenalidomide 25 mg/day for 21 days every 4 weeks, plus Prednisone 50 mg three times/week for 4 weeks) followed by 6 MPR cycles (Melphalan 2 mg and Prednisone 50 mg three times/week, for 4 weeks plus Lenalidomide 10–15 mg/day for 21 days every 4 weeks) and maintenance with Lenalidomide alone (10 mg/day for 21 days every 4 weeks). Two different dose-levels of Lenalidomide were tested in combination with MP: 15 mg (dose-level 1) and 10 mg (dose-level 2). Each cohort included 12 patients, with additional 22 patients enrolled at dose-level 2. Patients were evaluated for efficacy and toxicity after completion of at least 2 MPR cycles. Forty-six patients (median age 75, range 65–88) were enrolled. Thirty-six patients were evaluable after a median of 7 cycles and a median follow-up of 8.5 months. During RP induction, the most frequent grade 3–4 hematological adverse events were neutropenia (19%), anemia (11 %), thrombocytopenia (6%). During MPR consolidation, grade 3–4 adverse events were neutropenia (45%), and thrombocytopenia (3%). Neutropenia was increased by the addition of melphalan, but both thrombocytopenia and anemia were reduced. Non-hematological toxicities were more frequent during RP cycles and reduced during MPR cycles (cutaneous rash and infections). After RP induction, at least partial response (PR) rate was 67%, at least very good partial response (VGPR) was 17%. After 2 MPR cycles, PR rate increase to 72%, including 22% of patients who achieved at least a VGPR. Conclusions. Induction with RP followed by consolidation with MPR showed a manageable safety profile and reduced the risk of anemia, thrombocytopenia and non-hematological toxicity in unfit elderly myeloma patients. These data will be updated at the meeting. Disclosures: Palumbo: Celgene Srl: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janseen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide in combination with melphalan for multiple myeloma patients at diagnosis. Guglielmelli:Celgene: Honoraria; Janseen-Cilag: Honoraria. Gay:Celgene: Honoraria. Cavallo:Celgene: Honoraria. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janseen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Vorinostat (V) In Combination With Bortezomib (B), Doxorubicin (D) and Dexamethasone (D) (VBDD) In Patients With Refractory Or Relapsed Multiple Myeloma: An Interim Phase I/II Analysis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3202-3202
Author(s):  
Martina Kleber ◽  
Dagmar Wider ◽  
Kristina Keller ◽  
Barbara Groß ◽  
Heike Reinhardt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Off Label Use ◽  
Hdac Activity ◽  
Deacetylase Inhibitor ◽  
Level 1 ◽  
Level 2 ◽  
Label Use

Abstract Introduction The combination of bortezomib, doxorubicin and dexamethasone (BDD) is well tolerated and induces a high overall response rate (ORR). Preclinical studies have demonstrated that vorinostat, a histone deacetylase inhibitor, is synergistic with bortezomib and doxorubicin. The aim of this phase I/II study was to determine the tolerability and activity of the combination of BDD with vorinostat (VBDD) in relapsed/refractory multiple myeloma (MM). Methods Patients received escalated vorinostat-doses (provided by MSD) at 100mg (dose level 0), 200mg (dose level +1) and 300mg (dose level+2) on days 1-4, 8-11, 15-18, combined with bortezomib 1.3mg/m2 day 1,8,15 (provided by Janssen), dexamethasone 40mg day 1,8,15,22 and doxorubicin on 9mg/m2 day 1+8. The primary objective was the maximum tolerated dose (MTD; 3+3 dose escalation design). Secondary objectives were safety, response assessed by EBMT and IMWG criteria, progression-free survival and overall survival. Correlative endpoints include prognostic MM-parameters, organ function, QoL-, comorbidity-assessments and translational studies (e.g. HDAC-activity in PB MNCs, Figure 1). Dose limiting toxicities (DLTs) were defined as any possibly drug related adverse events (AEs) ≥grade 3 (CTCAE) within the 1st cycle. After completion of 6 cycles, patients could continue with bortezomib maintenance therapy or proceed to (most often 2nd) ASCT. Results To date, 18/30 patients have been enrolled (median age 63 years [range 54-75], 55% men). The median Karnofsky Performance Status was 90% (range 70-100%). Median prior therapy lines were substantial with 3 (range 1-8): bortezomib, thalidomide or lenalidomide were given in 88% and 24% each, respectively; 94% of patients had undergone prior SCTs. Cytogenetic abnormalities included del(17p) (n=2), t(4;14) (n=2), gain(1q) (n=2), t(11;14) (n=4) and hyperdiploidy (n=7). No DLTs have been observed to date; with 3 patients each being included in dose level 0 and dose level +1 and the following patients safely proceeding to dose level +2. Six SAEs occurred in 4/18 patients (22%): bacteraemia (n=1) and herpes zoster reactivation (n=1) were suspected to be related to all VBDD-drugs. No causal relationship to study drugs was suspected for pneumonia (n=2), 1 syncope and 1 death due to PD with persisting plasma cell leukemia. The ORR (>PR) and clinical benefit rate (SD, PR, CR) was 65% and 89%, respectively. At a median follow-up of 8 months (range 3-23), there have been only 2 patients with PD (refractory MM + plasma cell leukemia). The analysis of HDAC activity after VBDD initiation demonstrated downregulation in 6/8 (75%) patients (Figure 1). Further analyses will determine, whether HDAC activity and treatment response may correlate and whether this HDAC downregulation may precede and/or indicate depth of response Conclusions VBDD is a well tolerated and effective regimen in heavily pretreated relapsed/refractory MM patients. There have been no observed DLT and the MTD of vorinostat was set at 300mg, with all reported SAEs being in line with the known safety profile of the investigated drugs. Our alternative vorinostat-schedule (dosing of 4 days on and 4 days off) induced excellent tolerability and seems to enhance the antimyeloma response, warranting completion of this study. Disclosures: Kleber: MSD, Janssen-Cilag: Research Funding. Off Label Use: Preclinical studies have demonstrated that vorinostat, a histone deacetylase inhibitor, is synergistic with bortezomib and doxorubicin. The aim of this phase I/II study was to determine the tolerability and activity of the combination of BDD with vorinostat (VBDD) in relapsed/refractory multiple myeloma. Vorinostat is off-label use for MM patients, all other drugs are in label use. Waesch:MSD, Janssen-Cilag: Research Funding. Engelhardt:MSD, Janssen-Cilag: Research Funding.

scholarly journals Phase I Trial of a Novel Conditioning Regimen Utilizing Total Marrow Irradiation (TMI) with Fludarabine-Melphalan for Patients with Relapsed Hematologic Malignancies Undergoing Second Allogeneic Stem Cell Transplantation (Allo-SCT)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Hongtao Liu ◽  
Bulent Aydogan ◽  
Yasmin Hasan ◽  
Amy Wang ◽  
Kamil Yenice ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Advisory Committees ◽  
Normal Tissues ◽  
Total Marrow Irradiation ◽  
Grade 3 ◽  
Relapse Rates

Background: Treatment options for relapse after allo-SCT remain limited with poor outcomes. Second Allo-SCT provides benefit to a small subset of patients (pts). However, relapse rates after second Allo-SCT are high and novel approaches to improve outcomes after second Allo-SCT are needed. Conventional total body irradiation (TBI) can reduce relapse rates, but greater radiation doses cannot be delivered safely without increasing the toxicity to surrounding normal tissues and organs. Total marrow irradiation (TMI) techniques permit dose escalation while substantially reducing doses delivered to normal tissues relative to conventional TBI. We conducted a phase I study to assess the feasibility of combining TMI with a fludarabine-melphalan conditioning regimen for second or beyond Allo-SCT to decrease relapse. Methods: Inclusion criteria required a matched/mismatched donor and relapse after previous allo-SCT. GVHD prophylaxis was tacrolimus and mycophenolate mofetil, plus ATG for mismatched donors (NCT02333162). From December 2015 to May 2020, twenty-two pts with were consented to this 3 + 3 phase I trial design; one pt failed to proceed and was replaced. 21 pts (18 AML, 2 MDS/MPN, one ALL) were treated with linac-based volumetric modulated arc therapy (VMAT) technique using 6 MV photons. TMI was provided twice daily at 1.5 Gy per fraction starting with a total dose of 6 Gy, with dose escalation to 9 Gy and 12 Gy. Mucositis was an adverse event of special interest and assessed by the WHO Mucositis Score on days 7, 14, 21, and 28 post-transplant to investigate the combined mucosal injury from alkylating chemotherapy and radiation. Results: Baseline characteristics are summarized in Table 1. The median age was 56 years. All had matched donors except for one mismatched unrelated donor. 6 pts were in CR2, 4 pts in CR3, and 11 pts had refractory disease prior to 2nd SCT. 3 pts treated on dose level 6 Gy had no DLTs. At dose level 2 (9 Gy), the first pt of the cohort of six pts had grade 3 mucositis as a DLT on day 7; it resolved by day 21. The first 2 pts at dose level 3 (12 Gy) had no DLT, but the 3rd pt had DLT of grade 3 mucositis on day 7, resolving by day 14. Two more pts were treated and none had DLT. A sixth pt with refractory disease was treated but had graft failure with concurrent bacterial, fungal, and viral infections. This pt also developed grade 3 mucositis on day 14 that progressed to grade 4 on day 21 but resolved by day 28. Thus, we determined the MTD for TMI was 12 Gy; 9 Gy was an alternative dose for less fit or older pts. SCT outcomes were listed in Table 1. As mentioned above, 1 pt had primary graft failure, and one pt failed to have platelet engraftment due to early relapse. 11 pts developed aGVHD with cumulative aGVHD at 58%, and 4 pts developed cGVHD with cumulative cGVHD at 33%. With median follow up of 11 months (1 - 30 months), 6 pts had disease relapse after a median of 205 days (46-464 days); 10 pts have died (5 from PD; 2 from infection, 1 from GVHD, 1 from PTLD, 1 from second malignancy). Two year PFS and OS were 48% and 50% respectively, which compare favorably to the 2 years PFS and OS of 17.5% and 22.6% from our historical data with 65 pts who had 2nd Allo-SCT prior to this TMI trial at our center (Fan et al. Exp Hematol Oncol 2019). Conclusion: We recommend 12 Gy of VMAT-TMI as the MTD combined with fludarabine-melphalan (140mg/m2) as a conditioning regimen for second allo-SCT. Grade 3-4 mucositis was transient, peaking at days 7-14, and resolving by day 21-28. 9 Gy may be appropriate for less fit or older pts. The 2 year PFS and OS of 48% and 50% after second Allo-SCT for this novel TMI-based regimen are sufficiently encouraging to warrant further study. Table 1 Disclosures Liu: Agios: Honoraria, Other: Regional Advisory board meeting; BMS: Research Funding; Karyopharm: Research Funding. Stock:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Research to Practice: Honoraria; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Research Funding; Novartis: Research Funding; Leukemia and Lymphoma Society: Research Funding; American Society of Hematology: Honoraria; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees. Larson:Novartis, Takeda, CVS/Caremark, Celgene, Amgen, Epizyme: Consultancy; Astellas, Celgene, Daiichi Sankyo, Novartis, Rafael Pharmaceuticals, Cellectis, Forty Seven: Research Funding. Kline:Verastem: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite/Gilead: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding. Riedell:Novartis: Consultancy, Honoraria, Research Funding; Kite Pharmaceuticals/Gilead: Honoraria, Research Funding; Bayer: Honoraria; Celgene/Bristol-Myers Squibb Company: Honoraria, Research Funding; Verastem Oncology: Honoraria; Morphosys: Research Funding; Karyopharm Therapeutics: Honoraria. Bishop:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Speakers Bureau; CRSPPR Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Honoraria, Speakers Bureau.

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

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 175-175 ◽  
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.

Sign in / Sign up

Export Citation Format

Share Document