Phase I Trial of CG53135-05 to Prevent Mucositis in Patients Undergoing High-Dose Chemotherapy (HDCT) and Autologous Peripheral Blood Stem Cell Transplantation (PBSCT).

Abstract Mucositis is a painful side effect of many transplant conditioning regimens used in HDC and PBSCT. This complication often requires treatment with potent narcotic analgesics and may even require intravenous patient-controlled analgesia (PCA) for adequate pain relief as well as total parenteral nutrition (TPN). Infections in this setting may also result from disruption of the mucosal barrier with subsequent migration of intestinal bacteria into the blood stream. Previous treatments with oral rinses and topical applications of soothing gels have largely been ineffective. Recently, a breakthrough class of drugs in the fibroblast growth factor (FGF) family holds great promise in more effectively ameliorating or even preventing oral mucositis (OM). We report on the results of a Phase I trial with CG53135-05, a novel investigational protein therapeutic (FGF-20) that promotes epithelial and mesenchymal cell proliferation in vitro and has demonstrated activity in animal models. 14 patients (ages 25–75) undergoing HDCT with PBSCT were treated with escalating doses of study drug, including 0.1 mg/kg, 0.2 mg/kg and 0.33 mg/kg (concentrations are determined by the UV method which are equivalent to 0.3, 0.6, and 1 mg/kg by the Bradford method previously used). Conditioning regimens used included melphalan (Mel 200), cyclophosphamide, carmustine and etoposide (CBV), carboplatin and thiotepa (CT), cyclophosphamide, etoposide and carmustine (CEC) and busulfan/cyclophosphamide (targeted BuCy). The primary objective of this phase I trial was to evaluate safety, tolerability and pharmacokinetics of CG53135-05. Patients (pts.) were also scored daily for presence of OM using both the WHO and OMAS (oral mucositis assessment scale) grading scales. 7/14 pts. in this study experienced no OM (including 2 Mel 200 patients), 5 pts. experienced only grade 1 OM. while 2 pts. (both treated with Mel 200) experienced grade 3 OM, and no pts. experienced grade 4 OM. 1 pt. experiencing grade 3 OM required TPN. Only 4 pts. experienced diarrhea that lasted more than 4 days and only 1 pt. had gut mucositis-associated (E. coli) bacteremia. The median day of engraftment (ANC>500/uL) occurred on day 14 (range: day 11–19). Patients tolerated the study drug well with no significant side effects up to a dose of 0.33 mg/kg. At that dose, 2 pts. experienced an infusional reaction consisting of fevers, nausea, and mild hypotension. Pharmacokinetics were measured at all dose levels and will be presented. CG53135-05 is a member of a breakthtrough drug class (FGF family) that was well tolerated in autologous stem cell transplant patients at doses up to 0.33 mg/kg with apparent clinical effects in ameliorating or preventing OM - 12/14 pts, thus, avoided severe (grades 3–4) mucositis following HDCT. A larger Phase II clinical trial is planned.

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Final analysis of the phase II, randomized, double-blind, placebo-controlled trial of single dose velafermin (CG53135–05) for the prevention of oral mucositis

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.6537 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 6537-6537 ◽

Cited By ~ 4

Author(s):

M. W. Schuster ◽

E. Anaissie ◽

D. Hurd ◽

W. Bensinger ◽

J. Mason ◽

...

Keyword(s):

Stem Cell ◽

Single Dose ◽

Phase Ii ◽

Oral Mucositis ◽

Conditioning Regimen ◽

Study Drug ◽

High Dose ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Grade 3

6537 Background: Oral mucositis (OM) is a commonly occurring side effect of high-dose chemotherapy (HDCT) in patients (pts) undergoing autologous hematopoietic stem cell transplant (AHSCT). Velafermin, recombinant human fibroblast growth factor 20, is being investigated for prevention of OM. Velafermin promotes epithelial and mesenchymal cell proliferation in vitro and in vivo. Methods: A phase II trial was conducted to evaluate safety, efficacy, and pharmacokinetics (PK) of velafermin. Inclusion criteria: pts undergoing HDCT and AHSCT with or without total body irradiation (TBI) were enrolled. Velafermin at 0.03, 0.1, or 0.2 mg/kg or placebo was administered as single dose IV at 24h after stem cell infusion. Safety and PK were assessed. Pts were scored daily for presence of OM using the WHO grading scale. The primary endpoint was the incidence of Grade 3/4 OM. Results: A total of 212 pts were randomized to either placebo (n=51) or velafermin at 0.03 (n=50), 0.1 (n=56), or 0.2 (n=55) mg/kg (intent-to-treat or ITT sample). 206 pts (97%) received study drug or placebo. Pt diagnoses included multiple myeloma (57%), non-Hodgkin’s (25%), or Hodgkin’s (11%) lymphoma and 13 pts (6%) received TBI as part of the conditioning regimen. The Grade 3/4 OM incidence rates (%) in the placebo or velafermin arms (0.03, 0.1, and 0.2 mg/kg) were 37, 18, 38, and 36, respectively. The primary analysis of dose dependent reduction of severe OM was not statistically significant (p = 0.549). However, velafermin at 0.03 mg/kg did reduce the incidence of Grade 3/4 OM when compared to placebo alone (p = 0.031). Duration of Grade 3/4 OM was reduced significantly in the 0.03 mg/kg when every pt was evaluated or in the 0.1 mg/kg dose when only pts with Grade 3/4 OM were included in the analysis (p = 0.037 and 0.014, respectively). A total of 5 related SAEs (3 in 0.1 mg/kg, 1 in 0.03 mg/kg, and 1 in placebo cohort) occurred within 4hr of study drug infusion. All symptoms were transient. Conclusion: Single dose velafermin at 0.03mg/kg is may be active in reducing CT induced severe OM in AHSCT pts. Safety profile supports continuing study to define the optimal dose for prevention of severe OM. A new Phase II study will be conducted to confirm velafermin activity at 0.03mg/kg dose. [Table: see text]

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A Phase I Trial of Two Sequence-Specific Schedules of Decitabine and Vorinostat in Patients with Acute Myeloid Leukemia (AML).

Blood ◽

10.1182/blood.v110.11.908.908 ◽

2007 ◽

Vol 110 (11) ◽

pp. 908-908 ◽

Cited By ~ 2

Author(s):

Karen W.L. Yee ◽

Mark D. Minden ◽

Joseph Brandwein ◽

Aaron Schimmer ◽

Andre Schuh ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Phase I Trial ◽

Concurrent Schedule ◽

Maximum Tolerated Dose ◽

Leukemic Cells ◽

Clinical Activity ◽

Cell Transplant ◽

Sequential Schedule ◽

Grade 3

Abstract Background: Epigenetic silencing of genes has been documented in AML. This phase I trial evaluates the safety, tolerability, and maximum tolerated dose (MTD) of two schedules of administration of the hypomethylating agent decitabine in combination with the pan-selective histone deacetylase inhibitor vorinostat. Methods: Patients receive escalating doses of oral vorinostat administered either sequentially [100 mg bid (n=4), 200 mg bid (n=4), or 200 mg tid (n=8) Days 6–21] or concurrently [100 mg (n=3) or 200 mg (n=6) bid Days 1–21 or 200 mg tid (n=2) Days 1–14] with decitabine (20 mg/m2/d IV Days 1–5) every 28 days. Results: Twenty-seven patients with AML have been treated. Median age was 67 years (range, 32–82 years). Median ECOG status 1 (range, 0 to 2). Eighteen patients (67%) had received prior therapy (median, 1 regimen; range, 0 to 4 regimens); 3 had received a prior allogeneic stem cell transplant. A total of 85 cycles have been administered, with a median of 2 cycles (range, 1 to 13 cycles); 10 patients (37%) have received 3 or more cycles of therapy. One of 7 patients treated at dose level 3 of the sequential schedule developed dose-limiting toxicities (DLT), consisting of grade 3 fatigue, weakness, and mucositis. Therefore, the MTD was not reached in the 3 planned dose levels of the sequential schedule. One DLT (grade 3 fatigue) occurred in 6 patients treated at dose level 2 of the concurrent schedule. Most common drug-related non-hematological toxicities of any grade (all CTCAE grades 1 or 2) were nausea (71%), fatigue (54%), diarrhea (54%), vomiting (42%), anorexia (25%), constipation (13%), abdominal pain (13%), dehydration (13%), and headache (13%). No other non-hematological grade 3 or 4 toxicities were observed. Of the 25 evaluable patients, one patient achieved an incomplete CR (without neutrophil recovery), one a morphologic leukemia-free state (without blood count recovery), and three partial remissions (1 achieved red cell transfusion independency and a second normalization of platelet counts). Seven of these patients remain on study for 2.7 to 13.5+ months. Correlative studies examining histone acetylation and gene promoter methylation in leukemic cells at baseline and after treatment, as well as plasma pharmacokinetic levels for both decitabine and vorinostat are being evaluated. Conclusions: The combination of decitabine and vorinostat is safe, well-tolerated, and has clinical activity in patients with AML. Enrollment is ongoing.

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Phase I/II Dose-Escalation Study of Tositumomab and Iodine I 131 Tositumomab for Relapsed/Refractory Classical or Lymphocyte-Predominant Hodgkin’s Lymphoma: Feasibility and Initial Safety

Blood ◽

10.1182/blood.v112.11.3059.3059 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3059-3059 ◽

Cited By ~ 5

Author(s):

Heather A. Jacene ◽

Yvette L. Kasamon ◽

Richard F. Ambinder ◽

Wayne Kasecamp ◽

Donna Serena ◽

...

Keyword(s):

Stem Cell ◽

Adverse Events ◽

Phase I ◽

Dose Escalation ◽

Hodgkin’S Lymphoma ◽

Hodgkin's Lymphoma ◽

Cd20 Expression ◽

Grade 3 ◽

Experienced Grade ◽

131I Tositumomab

Abstract Objective : CD20 has been recently recognized as a potential immunotherapeutic target in Hodgkin’s lymphoma (HL), being expressed in all malignant cells in lymphocyte-predominant HL (LPHL), a subset of classical HL (cHL), and in normal surrounding B-cells. Recent data also suggest that the cancer stem cell in cHL is phenotypically distinct from Reed-Sternberg cells and expresses B-cell antigens including CD20 (Jones RJ et al, Blood2006; 108: abstract 470). Given the single agent activity of the unlabeled antiCD20 monoclonal antibody, rituximab, in HL, we are conducting a phase I/II study of tositumomab and Iodine I 131 (131I-) tositumomab (BEXXAR ®, GlaxoSmithKline) for HL in the relapsed/refractory setting, regardless of tumor CD20 expression. We report on feasibility and initial safety. Methods : Separate dose-escalation studies were performed for patients with and without prior stem cell transplantation, starting at 55 and 75 cGy total body radiation doses (TBD), respectively. Dosimetry imaging studies were performed after administration of 450 mg tositumomab and 5 mCi 131I-tositumomab. Patients then received a single patient-specific therapeutic dosage of 450 mg tositumomab and 131I-tositumomab. The TBD was escalated or de-escalated based on a continual reassessment method (CRM). Results : Seven patients with relapsed/refractory disease (6 cHL, 1 LPHL; mean age 36 ± 9) have been enrolled. Four patients with cHL were negative for CD20 on malignant Reed-Sternberg cells and two had mixed expression. Three patients who had failed transplant received a 55 cGy TBD of 131I-tositumomab and three ineligible for transplant received 75 cGy. No dose-limiting toxicities were observed and based on the CRM, the TBD was escalated to 79 cGy for the post-transplant group and to 87 cGy for the no transplant group. To date, one in the next post-transplant cohort received 79 cGy and experienced grade 1 thrombocytopenia and grade 3 lymphopenia with count recovery. No adverse reactions occurred during infusion of unlabeled or radiolabeled tositumomab, and the agent was generally well-tolerated in all dosing cohorts. The expected hematologic adverse events were common and are summarized in the Table. No patients experienced grade 3 or 4 non-hematologic toxicity. One patient had grade 1 or 2 fever, chills, joint and muscle pain suggesting possible human anti-mouse antibody formation and immune complex mediated inflammation. One patient with LPHL had a complete response, two with cHL had stable disease (1 mixed CD20 expression, 1 CD20 negative) and 4 with cHL had progressive disease (1 mixed CD20 expression, 3 CD20 negative) at 12 weeks post-131I-tositumomab. Conclusions : Tositumomab and 131I-tositumomab can be safely administered to patients with relapsed/refractory HL. Major toxicities are hematologic, similar to its effect in patients with non-Hodgkin’s lymphoma. The CRM was used successfully for determining TBD for subsequent cohorts, and the transplant recipients have tolerated higher doses than those previously reported in non-Hodgkin’s lymphoma. These encouraging preliminary data support further dose escalation and suggests some therapeutic effect of tositumomab and 131I-tositumomab against HL. Hematologic Adverse Events All (n=7) Grade Range of Duration of Grade 3/4 Toxicity (days) 1/2 3 4 Thrombocytopenia 6 0 1 1 7–34 Neutropenia 2 1 0 1 7 Lymphopenia 7 2 3 2 1–35 Anemia 2 1 1 0 4

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Phase I Study of Bortezomib(Bz), Pegylated Doxorubicin(DOX) and Dexamethasone(dex); ( VDD) with Escalating Doses of Cyclophosphamide(Cy) in Patients with Newly Diagnosed Myeloma.

Blood ◽

10.1182/blood.v114.22.617.617 ◽

2009 ◽

Vol 114 (22) ◽

pp. 617-617

Author(s):

Melissa Alsina ◽

Rachid Baz ◽

Jose L Ochoa ◽

Jyotishankar Raychaudhuri ◽

Kara Kosakowski ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Phase I ◽

Research Funding ◽

Stem Cell Mobilization ◽

Cell Transplant ◽

Newly Diagnosed ◽

Long Term Outcome ◽

Cell Mobilization ◽

Grade 3

Abstract Abstract 617 Background: The VDD treatment regimen has been shown to be highly effective as initial therapy for multiple myeloma. Given the established synergy between bortezomib and alkylating agents, incorporating an alkylator to VDD may increase the depth of response and may improve long term outcome. We report the results from a Phase I trial combining VDD with escalating doses of cyclophosphamide ( CVDD) in patients (Pts) with newly diagnosed myeloma. Methods: Pts received Bz 1.0–1.3 mg/m2 on days 1, 4, 8, 11, DOX 30mg/m2 on day 4, Dex 20 mg on days 1, 2, 4, 5, 8, 9, 11, 12 and Cy 250-750 mg/m2 on day 1, for up to eight 21-day cycles, at four planned dose levels (Cy/Bz: 250/1.0, 500/1.0, 750/1.0, 750/1.3). Dose-escalation proceeded (three-pt cohorts) depending on dose-limiting toxicities (DLTs) grade 3 non-hematologic toxicity; thrombocytopenia with platelets <10,000/mm3 on >1 occasion despite transfusion support; Grade 4 neutropenia for >5 days and/or resulting in neutropenic fever; inability to receive cycle 2/day 1 dose due to drug-related toxicity). Pts with Grade 2 peripheral neuropathy (PNY) were excluded. Responses were assessed by International Working Group criteria. Pts with at least partial response ( PR) and standard risk cytogenetics could proceed to autologous stem cell transplant (ASCT) after 6 cycles. Responsive pts with high risk cytogenetics defined as the presence of one of the following at diagnosis; deletion of chromosome 13 by cytogenetics, hypodiploidy, or t (4;14), t(14;16) or deletion of 17 p by FISH, completed 8 cycles of therapy. Results: 26 pts have been enrolled to date: 12 in phase l, and 14 additional pts at the maximum planned dose (MPD). Median age 60 yrs, 62% men, 50% IgG MM, 81% with ISS stage II/III. Pts have received a median of 6 cycles; 17 have completed all 6-8 cycles, 1 has discontinued therapy. No DLTs were observed in the phase I portion of study. Dose reductions in cycle 2 and beyond have occurred in 31% of patients. Toxicities to date have been manageable, including all Grade 3/4 hematological toxicities (4-35%), Grade 3 hand foot syndrome( 15%), Grade 3 pneumonia (8%), Grade 3 UTI (8%), and Grade 3/4 metabolic (19%). There were no grade 3/4 PNY. There was 1 treatment-related mortality secondary to infection. The overall response rate in patients that have completed at least 4 cycles of therapy (ORR; ≥PR) is 90%, including 57% ≥VGPR, and 24% CR. ORR and VGPR rates were similar in patients with standard or high risk cytogenetics. Nine patients have proceeded to transplant and all have had successful stem cell mobilization with G-CSF alone. Conclusions: CVDD produces high quality responses and is well tolerated in newly diagnosed MM pts, regardless of their cytogenetic status or ISS stage. MPD has been reached at CY 750 mg/m2, Bz 1.3 mg/m2, DOX 30 mg/m2, and Dex 20 mg, with phase II enrollment ongoing. Stem cell mobilization has been successful in all pts, with transplant course in pts otherwise unremarkable. Updated efficacy will be presented at the meeting. Disclosures: Alsina: Millenium: Research Funding, Speakers Bureau; Ortho Biotech: Research Funding, Speakers Bureau.

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Phase I trial study of bendamustine, ofatumumab, and pentostatin (BOP) as salvage regimen for patients with relapsed or refractory non-Hodgkin’s lymphoma or chronic lymphocytic leukemia.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e19005 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e19005-e19005

Author(s):

Colin Thomas ◽

Sameh Gaballa ◽

Martina DiMeglio ◽

Seyfettin Onder Alpdogan ◽

Matthew H. Carabasi ◽

...

Keyword(s):

Phase I ◽

Phase I Trial ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Electrolyte Imbalance ◽

Cell Transplant ◽

Salvage Regimen ◽

Common Grade ◽

Infusion Reactions ◽

Grade 3

e19005 Background: No standard salvage regimen exists for patients (pts) with relapsed or refractory (RR) NHL or CLL. Bendamustine, pentostatin and ofatumumab have activity in pts with CLL and NHL, but have not been combined as a single regimen. We conducted a phase I trial to assess the safety of this regimen. Methods: Pts with RR B-NHL or CLL were eligible. The design was a standard 3+3 using escalating doses of Bendamustine (50, 70, or 90 mg/m2 D1-2), Pentostatin (4 mg/m2 D1), and Ofatumumab (cycle 1: 300 mg D1; cycle 2-6: 1000 mg D2) every 28 days. Responses were assessed after cycle 3. Results: Ten pts were enrolled (6M/4F). Median age was 56 (range 37-65). Pts had follicular (FL) NHL (n = 2), CLL or SLL (n = 6), primary mediastinal B-cell lymphoma (PMBL) (n = 1), and extra-nodal marginal zone (MZL) NHL (n = 1). Pts had relapsed (n = 7) or refractory disease (n = 3) and received a median of 3 prior lines of therapy (range 1-4). Two CLL pts had high risk cytogenetics: 11p (n = 1) and 17p (n = 1). Most NHL pts (3/4) had stage 4 disease and all were refractory to rituximab. The ORR was 90% (PR = 5 pts: FL = 2, CLL/SLL = 3; CR = 4; CLL = 3, MZL = 1). One pt with PMBL progressed on treatment and died. One pt with CLL relapsed after 6 months. After a median follow up of 17 mo, the OS was 90% and PFS was 80%. Two pts (FL and CLL/SLL) subsequently underwent allogeneic stem cell transplant. DLT was not reached. Grade 3-4 toxicities included electrolyte imbalance (50%), neutropenia (30%), thrombocytopenia (30%), tumor lysis (20%), neutropenic fever (20%), and infusion reactions (10%). Common grade 1-2 toxicities were hyperglycemia (90%), thrombocytopenia (80%), nausea (80%), edema (80%), fatigue (80%) and neutropenia (70%). Conclusions: The BOP regimen is well tolerated and safe in pts with RR B-NHL or CLL. No DLT toxicity was reached at the highest bendamustine dose of 90mg/m2. Targeted therapies have largely supplanted the role of chemo-immunotherapy in the salvage setting. This trial was initiated in the pre-ibrutinib era and accrual to the planned phase II portion is on hold as pts now receive targeted therapy as salvage therapy. BOP might be an option for pts refractory to other strategies. Clinical trial information: NCT01352312.

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Pivotal Phase 2 Study of Weekly Vincristine Sulfate Liposomes Injection (VSLI, Marqibo®) in Adults with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL) in Second Relapse or Progressing Following Two Anti-leukemia Treatment Lines.

Blood ◽

10.1182/blood.v114.22.3088.3088 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3088-3088 ◽

Cited By ~ 1

Author(s):

Susan O'Brien ◽

Gary Schiller ◽

Lloyd E. Damon ◽

John Lister ◽

Farhad Ravandi ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplant ◽

Lymphoblastic Leukemia ◽

Single Agent ◽

Study Drug ◽

Cell Transplant ◽

Vincristine Sulfate ◽

Disease Response ◽

Grade 3

Abstract Abstract 3088 Poster Board III-25 Adult ALL is a disease of primarily young and middle-aged adults that is associated with a high relapse rate following initial remission induction and a short overall survival following relapse. Patients in second relapse must deal with the lingering toxicities of prior therapies, organ dysfunction secondary to extramedullary disease, and the absence of fully approved and standard of care therapies for this advanced disease setting. Realistic goals of treatment in second relapse include eradication of leukemia, bridging to stem cell transplant, and prolongation of survival. Vincristine is active against leukemia and is typically used as part of multi-agent regimens to treat relapsed disease, but the pharmacokinetic profile and dosing cap are suboptimal and contribute to poor disease control and abysmal overall survival. VSLI is a nanoparticle formulation of vincristine sulfate USP encapsulated in sphingomyelin/cholesterol liposomes called Optisomes™. The Optisomal formulation permits dose intensification beyond that attainable with conventional vincristine sulfate injection, USP (VSI). VSLI provides a long circulation time and slow release of encapsulated vincristine sulfate resulting in enhanced tumor penetration and concentration. Preclinical studies of VSLI showed enhanced efficacy versus VSI in a variety of solid and hematologic malignancies. VSLI has a maximum tolerated dose of 2.25 mg/m2 weekly with no dose cap, while conventional vincristine sulfate is dosed at 1.4 mg/m2 with a 2 mg dose cap. A previous study involving VSLI in relapsed ALL showed a complete response rate of 19%, suggesting activity in the relapsed setting and prompting further study. This international, multicenter, single-arm study has completed enrollment of its target 56 subjects at 21 centers in 4 countries over 27 months. Major endpoints include response rate (CR/CRi) and overall survival (OS). 56 adult subjects received single agent intravenous VSLI at a dose of 2.25 mg/m2 weekly with no dose cap. The highest single dose of VSLI given to date in this study was 5.22 mg contrasted to the 2 mg dose this subject would have received with conventional vincristine. Subjects were monitored for disease response every 4 weeks and could be treated until disease progression. Of the demographic data available for 48 subjects, 24 were female and 24 male with a mean age of 38.7 years (range 19.3-79.6). All subjects received at least one prior vincristine-containing regimen and 21 subjects (44%) received vincristine sulfate in two prior regimens. 18 subjects (37%) had a prior stem cell transplant and 2 subjects (4%) had 2 prior stem cell transplants before receiving single agent VSLI. 71% of subjects had an ECOG Performance Status of 1 or greater, with 21% ECOG 2 or 3. Seven subjects (15%) had evidence of extramedullary disease at study entry. At interim analysis, treatment with single agent VSLI produced morphologic and cytogenetic CR in several of these heavily pretreated subjects, suggesting significant activity of VSLI in second relapsed leukemia. Of investigator-reported responses on 48 subjects with data available to date, 71% have evidence of either disease response or disease stabilization and 29% have reported disease progression. Of the subjects experiencing CR/CRi, at least 5 subjects subsequently underwent allogeneic stem cell transplant after receiving VSLI. At the time of this abstract the median OS is estimated to be 4.7 months (Q1-Q3: 3.4-10.5) using Kaplan-Meier methodology. The 5 most frequently reported adverse event are peripheral neuropathy, 14.6% Grade 3 or 4 (100% attributed to study drug); constipation, 2.4% Grade 3 (100% attributed to study drug); nausea, no Grade 3 or higher; pyrexia, 9.8% Grade 3 (2.4% attributed to study drug); and febrile neutropenia, 34.2% Grade 3 or 4 (7.3% attributed to study drug). VSLI is a promising new agent for the treatment of acute lymphoblastic leukemia in second relapse, a situation where there is high unmet need and no approved therapies exist. VSLI may be used as a single agent as a bridge to transplant in these heavily pretreated, multiply-relapsed subjects, or considered as a substitute for conventional vincristine sulfate. The ability to complete enrollment rapidly internationally with compelling evidence of objective responses in this study underscores the enthusiasm for and importance of developing VSLI for the treatment of this orphan leukemia indication. Efficacy data and preliminary PK results from the target 56 subjects will be presented. Disclosures O'Brien: Hana Biosciences, Inc.: Consultancy. Hagey:Hana Biosciences, Inc.: Employment. Deitcher:Hana Biosciences, Inc.: Employment. Kantarjian:Hana Biosciences, Inc.: Consultancy.

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ML-18 High-dose chemotherapy supported by autologous stem cell transplant in relapsed and refractory primary CNS lymphoma

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab159.095 ◽

2021 ◽

Vol 3 (Supplement_6) ◽

pp. vi25-vi25

Author(s):

Motoo Nagane ◽

Nobuyoshi Sasaki ◽

Kuniaki Saito ◽

Keiichi Kobayashi ◽

Ryo Onoda ◽

...

Keyword(s):

Stem Cell ◽

Phase I ◽

Stem Cell Transplant ◽

High Dose Chemotherapy ◽

Autologous Stem Cell Transplant ◽

High Dose ◽

Cell Transplant ◽

Phase Ii Trials ◽

Treatment Indications ◽

Conditioning Regimens

Abstract While whole brain radiation therapy (WBRT) has been performed as consolidation therapy in primary central nervous system lymphoma (PCNSL), high-dose chemotherapy supported by autologous stem cell transplant (HDC/ASCT) is widely investigated today as an alternative treatment strategy, given the high risk for radiation-induced neurotoxicity in WBRT. Various conditioning regimens have been investigated in phase II trials, which report non-inferiority of HDC/ASCT in efficacy and preservation of neurocognitive function in comparison with WBRT. Besides its promising efficacy, treatment-related deaths are reported in 11% in patients treated by a conditioning regimen using thiotepa, busulfan and cyclophosphamide (TBC), which raises a concern for safety. Among several conditioning regimens, analysis using registry data of Japan Society for Hematopoietic Cell Transplantation has revealed that the use of conditioning regimens containing thiotepa was a positive factor for longer PFS. According to the result of a phase I trial in Japan which investigated HDC/ASCT using thiotepa and busulfan (BuTT), thiotepa was approved by the pharmaceuticals and medical devices agency (PMDA) on March 2020. In comparison with the TBC regimen, cyclophosphamide is omitted, and the dose of thiotepa is lower (250 mg/m2, 3 days in TBC; 5 mg/kg, 2 days in BuTT) in BuTT, therefore BuTT could be less toxic in comparison with TBC, and no treatment-related deaths were observed in the phase I study in Japan. Further investigation on the efficacy and safety of BuTT in actual clinical practice is warranted. We have constituted a multi-disciplinary team in our institution in order to perform HDC/ASCT using BuTT in relapsed/refractory PCNSL. Treatment indications are as follows; 65 years old or younger, previously treated by rituximab, methotrexate, procarbazine and vincristine (R-MPV), good organ function and neurological status. Future directions along with preliminary treatment results will be discussed at the meeting.

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A Randomized Placebo Controlled Phase II Trial of Prevention of Severe Oral Mucositis Using Single Dose Velafermin in Patients Receiving Myeloablative Therapy and Autologous Hematopoietic Stem Cell Transplant (AHSCT).

Blood ◽

10.1182/blood.v110.11.615.615 ◽

2007 ◽

Vol 110 (11) ◽

pp. 615-615 ◽

Cited By ~ 2

Author(s):

Michael W. Schuster ◽

J. Mehta ◽

E.K. Waller ◽

R.M. Rifkin ◽

I. Micallef ◽

...

Keyword(s):

Stem Cell ◽

Adverse Events ◽

Oral Mucositis ◽

Interim Analysis ◽

Safety Information ◽

Study Drug ◽

Controlled Study ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Safety And Efficacy

Abstract Oral mucositis (OM) is a commonly occurring side effect in patients (pts) undergoing AHSCT. Velafermin, recombinant human fibroblast growth factor-20, is under investigation for the prevention of severe OM. Previous studies demonstrated that velafermin at 30 mcg/kg was well tolerated and was effective in reducing the incidence of severe mucositis. The primary objective of this multicenter, randomized, double-blind, placebo controlled study was to confirm safety and efficacy of 30 mcg/kg velafermin for prevention of severe OM incidence (grade 3/4 OM based on the WHO grading system). The secondary objective was to evaluate safety and efficacy of 10 and 60 mcg/kg doses to better define the therapeutic range. Pts were randomized to receive placebo or velafermin at 30, 10 or 60 mcg/kg in a 3:3:1:1 ratio 24–36 hrs after stem cell infusion. Randomization was stratified by study center and OM risk factors identified from the previous placebo controlled study in a similar population including conditioning regimen and body mass index (BMI ≥30). Pts with multiple myeloma or lymphoma (≥18 y.o.) receiving ≥2X106 /kg CD34+ cells following chemotherapy with or without Total Body Irradiation (TBI) were eligible. OM status and safety data were collected for 30 days post treatment while mortality and disease progression were followed for 1 yr. An interim analysis by a data monitoring committee (DMC) was planned to assess safety and efficacy after 50% of pts completed the 30 day treatment period. A total of 390 pts who received melphalan (200 mg/m2) (n=239), BEAM (n=129), TBI (n=15), or other (n=7) were randomized and 384 pts were treated. The study drug was well tolerated in general and no pts discontinued study due to drug-related adverse events. There were 93 serious adverse events (SAEs) in 78 (20%) pts and no drug-related death was reported. Five infusion-related SAEs were reported including vasovagal episode (2), syncope (2), and anaphylactoid reaction (1). All 5 episodes occurred on the day of study drug infusion and resolved on the same day with no sequelae. Based on review of the results from the interim analysis, which included safety and efficacy data from 200 pts, the DMC recommended that the study continue to completion as planned. The last pt has completed the 30 day study period. The un-blinded results of the OM efficacy endpoints from velafermin treated groups or placebo as well as 30-day safety information from all pts will be reported.

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Phase III Intergroup Study of Lenalidomide (CC-5013) Versus Placebo Maintenance Therapy Following Single Autologous Stem Cell Transplant for Multiple Myeloma (CALGB 100104): Initial Report of Patient Accrual and Adverse Events.

Blood ◽

10.1182/blood.v114.22.3416.3416 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3416-3416 ◽

Cited By ~ 5

Author(s):

Philip L. McCarthy ◽

Kouros Owzar ◽

Edward A. Stadtmauer ◽

Sergio Giralt ◽

David D Hurd ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Maintenance Therapy ◽

Research Funding ◽

Progressive Disease ◽

Study Drug ◽

Phase Iii ◽

Cell Transplant ◽

Grade 5 ◽

Grade 3

Abstract Abstract 3416 Poster Board III-304 Relapse and/or progression of disease are the primary causes of treatment failure after autologous hematopoietic stem cell transplant (ASCT) for multiple myeloma (MM). The primary objective of CALGB 100104 was to investigate whether adding maintenance therapy would improve the time to progression (TTP). The study was powered to detect an improvement of 9.6 months (prolongation of TTP from 24 months to 33.6 months) in MM patients undergoing a single ASCT. Secondary objectives were the Complete Response conversion rate following maintenance initiation, the Overall Survival and the feasibility of long term lenalidomide maintenance therapy. Eligible MM patients were Durie-Salmon Stage I-III patients within 1 year of diagnosis, receiving at least 2 months of any induction therapy with response (Stable Disease (SD) or better) and ≤ 70 years of age. Patients with progressive disease prior to ASCT were not eligible for study. Patients underwent stem cell mobilization followed by Melphalan 200 mg/m2 and ASCT with a minimum of 2 × 106 CD34 cells/kg for stem cell infusion. Responding patients with SD or better were randomized at day 100 to 110 post ASCT to study drug versus placebo. Patients with progressive disease were not randomized. Randomized patients were stratified by elevated β2 microglobulin at diagnosis and prior thalidomide or lenalidomide use during induction therapy. The starting dose was 10 mg daily with an escalation at 3 months to 15 mg if tolerated. Study drug could be de-escalated by 5 mg daily if not tolerated. Patients could be maintained at 5, 10 or 15 mg as tolerated and were followed with monthly complete blood counts. Drug was held for neutropenia (Absolute Neutrophil Count (ANC) < 500/μl or thrombocytopenia (<30,000/ μl) and restarted after resolution of cytopenia(s). Patients were re-staged by blood and urine testing every 3 months, by skeletal survey and bone marrow testing yearly and remained on maintenance therapy until progression. A total of 568 pts were registered at centers from the following cooperative groups: CALGB (n=377), ECOG (n=132), and BMT-CTN (n=59). The study opened in 12/2004 with increasing annual accrual: 2005, n=33, (6%); 2006, n=62, (11%); 2007, n=137, (24%); 2008, n=214, (38%); 2009, n=122, (21%) and study closure on 07/03/09. The drop out rate before randomization at day 100 to 110 was projected to be 10-15% with an expected randomization of 462 patients. Among the 568 registered patients, 424 have been randomized, 81 have dropped out pre-randomization and 63 are pending randomization as of 08/06/09. Projected final randomization is approximately 475. Pooled Hematologic and Non-Hematologic Adverse Events (AEs) are available from 275 patients in both arms. Individual patients experiencing Hematologic AEs are as follows: Grade 3 (severe) n=43 (16%); Grade 4 (life-threatening) n=26 (9%); and no Grade 5 (lethal). Individual patients experiencing Non-Hematologic AEs are as follows: Grade 3 n=74 (27%); Grade 4 n=9 (3%); Grade 5 n=5 (2%). The most common Non-Hematologic AEs were infection, fever, rash and fatigue. The Data Safety and Monitoring Board (DSMB) will continue to monitor the study for AEs and determination of progression. This large Phase III study has successfully completed patient registration and is nearing completion of patient randomization at day 100 to 110 post ASCT through the cooperation of the Intergroup oncology and transplant clinical research groups. Further analysis will determine if maintenance therapy with lenalidomide (CC-5013) is of benefit for MM patients following single ASCT. Disclosures McCarthy: Celgene: Speakers Bureau. Off Label Use: Lenalidomide for maintenance therapy following autotransplant for multiple myeloma. Stadtmauer:Celgene: Speakers Bureau. Richardson:Millenium (Research Funding and Advisory Board), Celgene, Keryx, BMS, Merck, Johnson and Johnson (All Advisory Board): Membership on an entity's Board of Directors or advisory committees, Research Funding. Anderson:Millenium: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

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Phase I Dose-Escalation Study of SCH 900776 in Combination with Cytarabine (Ara-C) in Patients with Acute Leukemia

Blood ◽

10.1182/blood.v118.21.1531.1531 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1531-1531 ◽

Cited By ~ 1

Author(s):

Brian M. Thomas ◽

Scott H. Kaufmann ◽

Jacqueline M Greer ◽

Steven D. Gore ◽

Keith W. Pratz ◽

...

Keyword(s):

Dna Damage ◽

Stem Cell ◽

Phase I ◽

Research Funding ◽

Stem Cell Transplant ◽

S Phase ◽

Cell Transplant ◽

Acute Leukemias ◽

Flat Dose ◽

Grade 3

Abstract Abstract 1531 Checkpoint kinase (Chk1) is a serine-threonine kinase that is activated via phosphorylation in response to DNA damage and is critical to the regulation of cell cycle progression. Ara-C triggers sequential activation of ATR kinase and Chk1 ex vivo to induce the S phase slowing that accompanies Ara-C treatment. Inhibition of Chk1 may abrogate S phase slowing, thereby preventing repair of Ara-C-induced DNA damage and potentiating the antitumor activity of Ara-C. The Hsp90 inhibitor tanespimycin (17-AAG) has been shown to enhance the cytotoxicity of Ara-C in part through Chk1 downregulation (RA Mesa et al., Blood 2005). While a phase I trial of Ara-C plus 17-AAG resulted in decreased blast cell Chk1 phosphorylation, drug toxicities precluded the clinical use of tanespimycin (SH Kaufmann et al., Haematologica, in press 2011). We have now tested the selective Chk1 inhibitor SCH 900776 (SCH 776) in combination with Ara-C in a Phase I dose-escalation trial in 24 adult patients with relapsed and refractory acute leukemias. AML (21) ALL (2) CML-BC (1) Male/Female 9/12 1/1 1/0 Age (range) 57 (23–73) 30, 63 36 Previous Ara-C 19 0 1 Relapsed 8 1 0 No. Prior CRs 2 (1–3) 2 0 Prior Stem Cell Transplant 6 0 0 Refractory 13 1 1 No. Prior Regimens 2 (1–4) 3 3 Prior Stem Cell Transplant 1 0 0 Secondary AML 8 0 0 MDS/MPD 6 0 0 Treatment-Related 2 0 0 Adverse Genetics 13 1 1 Single cytogenetics 3 1 0 Complex cytogenetics 11 0 1 Patients received Ara-C 667 mg/m2 on days 1–3 and 10–12 via 72-hour IV infusion along with SCH 776 on days 2, 3, 11, and 12 over 15 min IV starting at 10 mg/m2 (n=3) escalated to 20 mg/m2 (n=3), 40 mg/m2 (n=6), 56 mg/m2 (n=6), and flat dose of 140 mg (n=6) administered over 30 min IV. Maximal administered dose was achieved at 140 mg due to grade 3 prolonged QTc interval (n=1) and grade 3 hand-foot skin reaction (n=1). None of the expected mucosal or marrow toxicities of timed sequential Ara-C were exacerbated by SCH 776. Complete tumor clearance from day 14 bone marrow was detected in 13/24 (54%). CR plus CRi occurred in 7 patients (29%), with 6 of those CRs occurring at 40 mg/m2 or higher (response rate 40% for ≥ dose level 3). Examination of sequential samples of marrow blasts harvested pretreatment (day 0), 24 hours after initial Ara-C infusion prior to SCH 776 (day 2), and 2 hours after the second SCH 776 administration (day 3) demonstrated increased phosphorylation of Chk1 at Ser317 or Ser345 beginning at 40 mg/m2 consistent with the presence of unrepaired damage and further ATR activation. Pharmacokinetic (PK) data in each cohort showed lack of significant accumulation of SCH 776 in plasma. We plan for a randomized Phase II trial with 100 mg flat dose (or equivalent of 56 mg/m2) of SCH 900776 to assess any contributions to net Ara-C cytotoxicity and efficacy in relapsed and refractory acute leukemias. Disclosures: Gore: Celgene: Consultancy, Equity Ownership, Research Funding. Loechner:Merck Research Laboratories: Employment. Horowitz:Merck Research Labs: Employment, stock. Karp:Schering Merck: Research Funding.

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