scholarly journals Multicentre, Open Label, Randomized Phase III Study of Cpi-613® (devimistat) in Combination with High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) in Older Patients (≥ 60 years) with Relapsed / Refractory Acute Myeloid Leukemia (AML) - Armada 2000 (AML003) Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2658-2658 ◽  
Author(s):  
Timothy S. Pardee ◽  
Sanjeev Luther ◽  
Marc E. Buyse ◽  
Bayard L Powell ◽  
Jorge E. Cortes
Keyword(s):  
Complete Remission ◽  
Phase I ◽  
Phase Ii ◽  
Older Patients ◽  
Research Funding ◽  
Phase Iii ◽  
High Dose ◽  
Open Label ◽  
High Dose Cytarabine ◽  
Refractory Aml

Background: Despite recent advances, outcome of patients with AML, particularly the older ones, remains poor. This is in part because of adverse features more frequently associated with AML in this patient population. Older patients with AML have high mortality (>90%). This is driven by the fact that over 50% of patients will experience a relapse, and most relapsed patients will die from AML within a year. There is no consensus standard treatment for relapsed or refractory disease, highlighting the high unmet need for these patients. Devimistat is a novel lipoic acid analogue that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase. This inhibits mitochondrial respiration and cause hyper-phosphorylation of PDH and activation of adenosine monophosphate activated kinase (AMPK) in AML cells. The ARMADA 2000 trial seeks to leverage the unique mechanism of action of this agent to improve the outcomes for older patients suffering from relapsed or refractory AML. To date devimistat has been given to more than 108 relapsed or refractory AML patients in multiple clinical trials (phase I and phase II). These studies suggest that devimistat can be safely combined with high dose cytarabine and mitoxantrone in relapsed or refractory AML patients. The possible beneficial effect in older patients was demonstrated by the dose response relationship seen in older but not younger patients. The combined efficacy result from 23 treated patients (≥ 60 years) on either of phase I or phase II studies of devimistat and high dose cytarabine and mitoxantrone (CHAM) showed complete remission (CR) rate of 48%, CR + CRi of 52% and median overall survival (OS) of 12.4 months [interim result of this study was presented at EHA Annual Meeting 2018, for further details please refer: Analysis of phase I and pilot phase II data reveal 2,000 mg/m2 as the optimal dose of CPI-613 in combination with cytarabine and mitoxantrone for elderly patients with relapsed or refractory AML]. Given the favorable safety profile of CHAM with the promising response results achieved in these trials, further evaluation of devimistat in AML is warranted. The current study evaluates devimistat in combination with high dose cytarabine and mitoxantrone (CHAM) in older patients with relapsed or refractory AML. Method: This is a multicentre, open label, randomized phase III study of devimistat in combination with high dose cytarabine and mitoxantrone (CHAM) compared to high dose cytarabine and mitoxantrone (HAM) in older patients with relapsed/refractory AML. Eligible patients are male and female individuals who are 60 years and older with histologically documented AML that is relapsed from, or refractory to, prior standard therapies that include standard dose cytarabine or high dose cytarabine based induction cycle or no response after at least 3 cycles of a hypomethylating agent with or without venetoclax. Other key inclusion criteria include ECOG performance status 0-2 and expected survival >3 months. A total of 500 patients will be randomized in a 1:1 fashion between arms. Following completion of all planned induction and/ or consolidation therapy cycles, patients in remission on the CHAM arm will continue to receive devimistat during maintenance cycle(s) until disease recurrence, availability of stem cell transplant, the advent of intolerable side effects, or patient withdrawal of consent. Primary endpoint of the study is complete remission (CR) of CHAM compared to HAM. Secondary endpoints include overall survival (OS), complete remission with partial hematologic recovery (CRh) and safety. Exploratory analysis will examine the expression of a gene signature from baseline marrow samples found to be predictive of response in the phase I study. Additional analysis will correlate the expression of several key proteins including PDH, KGDH, PDK1-4, SOD2 and CD79a in baseline marrow samples with response. Statistical analysis plan for this trial is summarized in Table 1 and Table 2. This study was initiated in November 2018 and planned at approximately 87 sites in more than 13 countries, recruiting 500 patients. The interim analysis of the study is expected to be completed as early as Q3 2020. Clinical trial information: NCT03504410 Disclosures Pardee: Rafael Pharmaceuticals: Consultancy, Research Funding; Karyopharm: Research Funding; Pharmacyclics/Janssen: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; CBM Bipharma: Membership on an entity's Board of Directors or advisory committees; Spherix Intellectual Property: Research Funding. Luther:Rafael Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Buyse:Rafael Pharmaceuticals: Consultancy. Powell:Rafael Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Janssen: Research Funding. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; BiolineRx: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Devimistat is not approved by the FDA for any indication and the clinical trial describes its use in AML.

Devimistat in combination with high dose cytarabine and mitoxantrone compared with high dose cytarabine and mitoxantrone in older patients with relapsed/refractory acute myeloid leukemia: ARMADA 2000 Phase III study

2019 ◽  
Vol 15 (28) ◽  
pp. 3197-3208 ◽  
Author(s):  
Timothy S Pardee ◽  
Sanjeev Luther ◽  
Marc Buyse ◽  
Bayard L Powell ◽  
Jorge Cortes
Keyword(s):  
Clinical Trial ◽  
Complete Remission ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Tca Cycle ◽  
Phase Iii ◽  
High Dose ◽  
High Dose Cytarabine ◽  
Acute Myeloid ◽  
Refractory Aml

Devimistat (CPI-613®) is an intravenously administered, novel lipoate analog that inhibits two key tricarboxcylic acid (TCA) cycle enzymes, pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes (KGDH). These complexes control TCA cycle entry of glucose and glutamine-derived carbons, respectively. Acute myeloid leukemia (AML) cells upregulate the TCA cycle in response to DNA damaging agents and treatment with devimistat increases sensitivity to them. A Phase I study of devimistat in combination with cytarabine and mitoxantrone produced a complete remission rate of 50% in patients with relapsed or refractory AML. In the combined Phase I/II experience, older patients with R/R AML treated with 2000 mg/m2 of devimistat had a 52% complete remission/complete remission with incomplete hematologic recovery rate and a median survival of 12.4 months. This report outlines the rationale and design of the ARMADA 2000 study, a Phase III clinical trial of devimistat in combination with high dose cytarabine and mitoxantrone compared with high dose cytarabine and mitoxantrone alone for older patients (≥60 years of age) with relapsed or refractory AML. Clinical trial registration: NCT#03504410

scholarly journals Therapeutic Manipulation of Cancer Cell Metabolism with the Mitochondrial Metabolism Inhibitor Cpi-613 in Addition to Chemotherapy Abrogates the Adverse Prognostic Effect of Age in Relapsed and Refractory AML

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1355-1355 ◽  
Author(s):  
Timothy Pardee ◽  
Scott Isom ◽  
Leslie Renee Ellis ◽  
Dianna S. Howard ◽  
Rupali Bhave ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase I ◽  
Older Patients ◽  
Median Overall Survival ◽  
High Dose ◽  
Younger Patients ◽  
Age Related ◽  
High Dose Cytarabine ◽  
Refractory Aml ◽  
Phase I And Ii

Abstract Background: Acute myeloid leukemia is an aggressive malignancy with poor outcomes especially in patients 60 years of age or older. This thought to be in part from increased resistance to chemotherapy in AML cells arising in an older host. One of the nine recognized biological hallmarks of aging is a decline in mitochondrial quality. The effect of exploiting this age-related metabolic vulnerability in relapsed AML has not been previously established. CPI-613 is a first-in-class agent that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, effectively impairing the TCA cycle. We have combined CPI-613 with high dose cytarabine and mitoxantrone in phase I and II clinical trials in over 100 patients with relapsed or refractory AML. Methods: To determine the effect of the addition of CPI-613 in older patients, the phase I and II datasets were combined and outcomes by age were analyzed and compared to age related outcomes in a historical dataset of patients treated with a high dose cytarabine, mitoxantrone and L-asparaginase but without CPI-613. In both trials, patients were given CPI-613 as a 2-hour infusion on days 1 through 5. Cytarabine was dosed at 3,000 mg/m² (if younger than 60) or at 1,500 mg/m² (if 60 years of age or older), given every 12 hours for 5 doses, starting on day 3 following the CPI-613 infusion. The mitoxantrone was dosed at 6 mg/m² and is given once daily following the first, third and fifth cytarabine doses. At day 14, nadir marrow was evaluated, and patients with residual disease could be re-treated as above or with an abbreviated 3-day cycle. Responding patients were eligible to receive up to 2 abbreviated 3-day consolidation cycles. The historical cohort was treated identically without CPI-613, except L-Asparaginase was given at a dose of 6,000 units/m2 following the last dose of cytarabine. Results: Patient characteristics are summarized in Table 1. In the historical dataset younger patients had a highly significant increase in median overall survival when compared to patients ≥60 years of age (figure 1A). In contrast, older and younger patients treated with CPI-613 in addition to the chemotherapy had no significant difference in median survival (figure 1B). Additionally, when outcome by dose of CPI-613 was analyzed, older but not younger patients had a significant improvement in survival when given a dose of 2,000 mg/m2 compared to those given 1,500 mg/m2 (figure 1C+D). Patients 60 years of age or older had a response rate of 55% and a median overall survival of 12.4 months when treated with a dose of CPI-613 of 2,000 mg/m2. Conclusions: Targeting mitochondrial metabolism exploits an age-related metabolic vulnerability in AML arising in older patients. These results have led to a randomized phase III trial of CPI-613 at 2,000 mg/m2 in combination with high dose cytarabine and mitoxantrone compared to high dose cytarabine and mitoxantrone alone in relapsed or refractory AML patients 60 years of age or older. Disclosures Pardee: Amgen: Speakers Bureau; Karyopharm: Research Funding; Celgene: Speakers Bureau; Rafael Pharmaceuticals: Employment; Novartis: Speakers Bureau. Ellis:Alexion: Speakers Bureau. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

2006 ◽  
Vol 24 (1) ◽  
pp. 136-140 ◽  
Author(s):  
Andrew J. Vickers ◽  
Joyce Kuo ◽  
Barrie R. Cassileth
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Cancer Patients ◽  
Phase Ii ◽  
Dose Finding ◽  
Phase Iii ◽  
High Dose ◽  
Free Text ◽  
Phase Ii Trials ◽  
Off Label

Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials.

Holmium-166 (166Ho)-DOTMP Skeletal Targeted Radiotherapy (STR™) with Melphalan and Autologous Peripheral Stem Cell Transplant (PBSCT) for Multiple Myeloma (MM).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 922-922 ◽  
Author(s):  
Mark Goodman ◽  
William I. Bensinger ◽  
Sergio Giralt ◽  
Donna Salzman ◽  
Katherine L. Ruffner ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Hemorrhagic Cystitis ◽  
Conditioning Regimen ◽  
Complete Response ◽  
Phase Iii ◽  
High Dose ◽  
Cell Transplant ◽  
Red Marrow

Abstract Background: 166Ho-DOTMP is a beta-emitting radiophosphonate that localizes specifically to the bone surfaces and can deliver high dose radiation both to the bone and bone marrow. Follow-up data from 3 clinical trials with STR as conditioning for patients with MM undergoing autologous PBSCT are presented. Methods: In 2 Phase I/II dose-escalation trials, 83 patients received a dose of 166Ho-DOTMP STR calculated to deliver 20, 30, or 40 Gy to the red marrow; 82 pts received melphalan (140 or 200 mg/m2) ± 8 Gy TBI (n=25), followed by PBSCT. As of June, 2004, 77 subjects have been followed for at least 48 months. In a separate Phase II dosimetry trial, 12 patients received two 30 mCi tracer doses of 166Ho-DOTMP STR to determine the reproducibility of biodistribution and pharmacokinetics (PK). All pts received a 25 Gy therapy dose with concurrent IV hydration and continuous bladder irrigation, followed by 200 mg/m2 melphalan and PBSCT. These patients have been followed for at least 18 months. Results: Up to 2.3 Ci/m2, 166Ho-DOTMP STR was given in the Phase I/II trials; 29/83 (35%) patients achieved complete response (CR) and overall response rate (CR + PR) was 64% (7 pts not evaluable). The Kaplan-Meier estimate of median survival is 5.2 years for all 83 patients. In patients who are at least 4 years post transplant who achieved a CR, the survival is 74% (n=27). In patients who achieved less than a CR at least 4 years ago, the survival is 34% (n=44). Dose-related radiation-induced kidney toxicity presented in some patients more than 6 months post-therapy. The dose of 166Ho-DOTMP STR in the Phase II dosimetry trial was 550 to 860 mCi/m2, 166Ho-DOTMP. Currently, 18 months of follow-up reveals no occurrence of hemorrhagic cystitis or > Grade 2 elevated creatinine. A CR rate of 17% with an overall survival of 92%, was observed. In 10 patients who received 166Ho-DOTMP STR 750 mCi/m2 ± 10% in the Phase I/II trial, the CR rate was 40%, and the 4-year survival was 70%. Monitoring for safety and duration of response is ongoing in all 3 trials. Conclusion: Follow-up from the Phase I/II trials confirms that 166Ho-DOTMP STR provides favorable efficacy and safety as part of the conditioning regimen for patients with MM undergoing PBSCT. A Phase III, randomized multicenter study is now open to enrollment, comparing the safety and efficacy of 166Ho-DOTMP STR plus melphalan to melphalan alone as conditioning for PBSCT in subjects with primary refractory MM who have failed to respond to induction therapy, including high-dose dexamethasone, and are within 18 months of diagnosis.

Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: Preliminary phase I/II results of ECHO-202/KEYNOTE-037.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4503-4503 ◽  
Author(s):  
David C. Smith ◽  
Thomas Gajewski ◽  
Omid Hamid ◽  
Jeffrey S. Wasser ◽  
Anthony J. Olszanski ◽  
...  
Keyword(s):  
Phase I ◽  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Advanced Disease ◽  
Alternative Therapy ◽  
Phase Iii ◽  
Open Label ◽  
Advanced Urothelial Carcinoma ◽  
Grade 3 ◽  
Line Of Therapy

4503 Background: Pembrolizumab (P), a PD-1 inhibitor, is active and well tolerated in platinum-treated, advanced urothelial carcinoma (UC). Epacadostat (E) potently and selectively inhibits indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-catabolizing enzyme that suppresses T-cell–mediated immune surveillance. IDO1 overexpression is associated with tumor progression and shortened patient (pt) survival. ECHO-202/KEYNOTE-037 is an open-label, phase I/II study of E + P in pts with advanced tumors. We report phase I/II efficacy and safety outcomes for the UC cohort at an October 29, 2016 data cutoff. Methods: Adult pts with advanced UC, prior platinum therapy (adjuvant or advanced disease setting) or alternative therapy (if platinum was not appropriate), and no prior checkpoint inhibitor therapy were eligible to participate. In phase I, pts received E (25, 50, 100, or 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) dosing was selected for phase II. Response was assessed in RECIST 1.1–evaluable pts. Safety was assessed in pts receiving ≥1 E + P dose. Results: A total of 40 pts (phase I, n = 5; phase II, n = 35) were evaluated. Median age was 67 years, 75% were men, 88% were white, 100% had prior platinum therapy, and 75% had 0–1 prior line of therapy for advanced disease. Preliminary ORR (CR+PR) and DCR (CR+PR+SD) for all efficacy-evaluable pts were 35% (13/37; all PR) and 57% (21/37; 13 PR, 8 SD), respectively; for pts with 0–1 prior line of therapy for advanced disease, ORR and DCR were 37% (10/27) and 63% (17/27). At data cutoff, 12/13 responses were ongoing (range, 1+ to 652+ days). PFS and biomarker analyses are ongoing. The most common TRAEs (≥10% of 40 pts) were fatigue (28%), rash (18%), and increased amylase (10%; asymptomatic). Grade ≥3 TRAEs occurred in 20% of pts (rash was the only grade ≥3 TRAE to occur in > 1 pt [n = 3]). Three pts discontinued due to TRAEs (grade 3 rash [n = 1]; grade 3 COPD exacerbation [n = 1], grade 2 diarrhea [n = 1]). Conclusions: E + P was generally well tolerated and associated with increased response compared with previously reported PD-1 inhibitor monotherapy in pts with advanced UC. A phase III UC study is planned. Clinical trial information: NCT02178722.

scholarly journals Induction Therapy with Everolimus in Combination with DHAP (Dexamethasone, High-Dose AraC, Cisplatinum) in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma: A Randomized, Placebo-Controlled Phase I/II Trial (HD-R3i)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2912-2912 ◽  
Author(s):  
Bastian von Tresckow ◽  
Andreas Hüttmann ◽  
Vladan Vucinic ◽  
Horst Mueller ◽  
Annette Plütschow ◽  
...  
Keyword(s):  
Placebo Group ◽  
Phase I ◽  
Board Of Directors ◽  
Phase Ii ◽  
Induction Therapy ◽  
Research Funding ◽  
High Dose ◽  
Classical Hodgkin Lymphoma ◽  
Advisory Committees ◽  
Support Research

Abstract Introduction: Induction chemotherapy followed by BEAM high dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplant (PBSC transplant) is standard of care for transplant-eligible patients with relapsed or refractory classical Hodgkin lymphoma (rrHL). However, approx. 50% of patients relapse and therefore, this strategy must be improved. As response to induction therapy is predictive of the outcome after HDCT, this trial aimed at improving the response to induction therapy by adding oral everolimus to time-intensified standard DHAP (Ever-DHAP). Methods: We included patients with histologically confirmed rrHL aged 18-60 years in this phase I/II trial. Dosage of everolimus was pre-determined in the phase I part with 10 mg/day given parallel to DHAP for 14 days within each of two cycles. The phase II part started as a randomized controlled trial comparing 50 patients in the everolimus group to 50 patients in a placebo group. The primary endpoint of the phase II part was the CT-based complete remission (CR-) rate after two cycles of Ever-DHAP. This CR-rate would be expected to be ≥ 40% if adding everolimus was effective. Secondary efficacy endpoints of the trial were PET-based CR-rate after two cycles of induction, progression-free and overall survival. Secondary feasibility endpoints were time to recovery, CTC-based adverse events, duration of induction therapy, discontinuation rates and the rates of successful PBSC collection. The trial was registered at ClinicalTrials.gov with ID NCT01453504. Results: From 7/2014 to 3/2018 we recruited a total of 59 patients in the phase II part. Because of poor recruitment the placebo group was closed in 9/2015 after 9 patients were randomized. These patients are analyzed in a descriptive way only. Of 50 patients in the everolimus group two were not evaluable because of retracting consent and not starting therapy; three additional patients discontinued Ever-DHAP because of toxicity. PBSC collection was successful in 37/39 documented patients receiving Ever-DHAP (95%). After two cycles of therapy we observed a CT-based CR in 12/45 patients of the everolimus group (27%) and in 2/9 patients of the placebo group (22%). A PET-based CR was achieved by 19/38 patients of the everolimus group (50%) and by 4/5 patients of the placebo group. In the everolimus group two patients had refractory disease (4%) and two died (4%), 3 and 4 months after starting but not related to Ever-DHAP. Final results and additional analyses will be presented. Conclusions: Adding everolimus to time-intensified DHAP is feasible, however, the Ever-DHAP regimen failed to show an improved efficacy. Disclosures von Tresckow: Novartis: Honoraria, Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; MSD: Honoraria, Other: Travel support, Research Funding. Hüttmann:Celgene: Other: Travel expenses; Roche: Other: Travel expenses. Viardot:Amgen: Consultancy; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Gilead Kite: Consultancy, Honoraria. Topp:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding. Borchmann:Novartis: Consultancy, Honoraria.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3855-3855
Author(s):  
Marina Ciomei ◽  
Lucia Zanetta ◽  
Federico Lussana ◽  
Erika Ravelli ◽  
Francesco Fiorentini ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Single Agent ◽  
Dose Titration ◽  
Advisory Committees ◽  
Secondary Resistance ◽  
Support Research ◽  
Refractory Aml

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

scholarly journals Temsirolimus in Combination with Bendamustine and Rituximab for the Treatment of Relapsed Mantle Cell and Follicular Lymphoma: Report on an Ongoing Phase I/II Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3930-3930
Author(s):  
Georg Hess ◽  
Ulrich Keller ◽  
Johannes Atta ◽  
Ulrich Bitz ◽  
Christian Lerchenmueller ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Response Rates ◽  
Phase Iii ◽  
Mtor Inhibition ◽  
Grade 3 ◽  
Ongoing Phase

Abstract Background: mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas. In relapsed MCL a phase III trial could prove superiority of Temsirolimus to standard options. Furthermore, in patients with follicular and diffuse large B-cell lymphoma, promising response rates could be observed (Smith et al, JCO 2010). Whereas combination to single agent Rituximab (R) improved efficacy (Ansell et al, Lancet Oncology 2011), there is limited information of the feasibility and efficacy in combination with chemotherapy. Bendamustine (B) has been shown to be effective in various lymphoma entities and has a beneficial side effect profile (Rummel et al, JCO, 2005). In the phase I of this trial, we have established that 50mg of Temsirolimus given 3 times weekly in a four week cycle could be safely added to BR (Hess, Leukemia, 2015). Here we report for the first time combined results of phase I and II of this trial. Methods: this is a multicenter, national, prospective trial. Inclusion criteria: patients were eligible if they had histologically proven FL or MCL, 1-3 prior treatment lines, no curative option available, no refractoriness to Bendamustine, measurable disease, ECOG < 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. Treatment consisted of Bendamustine 90mg/m² day 1-2, Rituximab 375mg/m² day 1 and Temsirolimus 50 mg day 2, 8, 15 of a 28d cycle. A total of 4 cycles was planned with interim staging after 2 cycles. Results: Overall 34 patients (pts) have been included until now (15 pts phase I, 19 pts phase II). Concerning clinical characteristics, median age was 71 years, with 25 MCL and 9FL, and a median number of 2 pretreatments (1-3). Overall the treatment was well tolerated, and toxicity was predominantly hematologic. In 118 evaluable cycles of chemotherapy the following hematologic grade 3 / 4 toxicities were noted: leukopenia (11 pts, 32%), neutropenia (8 pts, 24%), and thrombocytopenia (7 pts, 21%). Non-hematologic grade 3 / 4 observed in at least two patients were angioedema and decrease in blood potassium, infection, metabolic (4 events). AE's of special interest: pulmonary: rate of cough (4; 12%) and pneumonitis (1; 3%); gastrointestinal: diarrhea (6; 18%), nausea (13, 38%); general: fatigue (16; 47%), mucositis (13, 38%); bleeding: epistaxis (4; 12%), which all were predominantly grade 1 or 2. Response: currently, best responses were 8 CR (31%), 16 PR (62%) and 2 SD (8%) in 26 patients evaluable so far. Updated results will be presented at the meeting. Overall responses were 94% in MCL (7 CR, 10 PR, 1 SD) and 88% in FL (1 CR, 6 PR, 1 SD). After a median follow up of 13 months (mean: 21 months) median PFS is 18.6 months for the entire cohort, with 22 months for MCL and not reached in FL. Summary: In this ongoing phase II trial 50mg Temsirolimus (day 1,8,15) in combination with Bendamustine and Rituximab was well tolerated and feasible. A moderate dose of Temsirolimus to standard chemotherapy might be the optimal way to achieve the maximum efficacy with mTOR inhibitors; in fact excellent response rates suggest an additive effect of mTOR inhibition to BR. Even after the BTK inhibitor Ibrutinib has entered the clinical arena of MCL, this combined treatment represents a valuable additional option especially for patients with relapsed MCL Disclosures Hess: Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding; Janssen, Roche, , Celgene, Novartis: Consultancy. Keller:Roche: Consultancy, Honoraria; Pfizer: Consultancy. Witzens-Harig:Roche: Honoraria; Pfizer: Honoraria, Research Funding.

Relapsed and Refractory Acute Myeloid Leukemia (AML) Treated with AS1411 and Cytarabine: A Randomized Phase II Trial.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1935-1935 ◽  
Author(s):  
Robert Kenneth Stuart ◽  
Gary Acton ◽  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Cytogenetic Response ◽  
High Dose ◽  
In Vivo Models ◽  
Randomized Phase Ii ◽  
High Dose Cytarabine ◽  
Grade 3 ◽  
To Receive ◽  
Refractory Aml

Abstract Background: AS1411 is an aptamer that binds to nucleolin, which is upregulated and overexpressed in the cytoplasm and on the cell surface of cancer cells. Combination of AS1411 with cytarabine produces synergistic effects on AML cell lines and in vivo models. A phase I trial of AS1411 monotherapy in 30 patients with various advanced cancers revealed no dose-limiting toxicities and showed evidence of activity, including 2 responses among 12 patients with metastatic renal cancer. This phase II study evaluates the addition of AS1411 to high-dose cytarabine in relapsed and refractory AML. Methods: This open-label randomized phase II trial compares AS1411 plus cytarabine with cytarabine alone in patients with primary refractory or relapsed de novo or secondary AML who have received up to 3 previous induction cycles. Patients in cohort I were randomized in a 1:2 ratio to receive cytarabine (3,000 mg/m2/day) for 4 days or AS1411 (10 mg/kg/day) on days 1–7 plus cytarabine on days 4–7. Following safety assessment, a second cohort was to be randomized 1:2 to receive cytarabine 3,000 mg/m2/day) for 4 days or AS1411 at a higher dose (40 mg/kg/day) on days 1–7 plus cytarabine on days 4–7. Key study objectives are comparison of response rates and safety and tolerability between treatment groups. Patients not achieving a CR after one cycle of single agent cytarabine are eligible for a subsequent cycle of AS1411 plus cytarabine. Results: Thirty-three patients had been randomized by July 2008, all to the first cohort. Safety findings were available for 27 patients (9 in the cytarabine arm and 18 in the combination arm). Numbers of grade 3 and 4 adverse events per patient were 19 among 9 patients on cytarabine alone and 35 among 18 patients on AS1411 plus cytarabine. The main grade 3/4 toxicities reported were blood and lymphatic system disorders, particularly febrile neutropenia, neutropenia and thrombocytopenia; and infections and infestations. Induction deaths were 1/9 and 0/18, respectively. Response data were available for 20 patients. In the cytarabine-alone group, 0/7 patients achieved a CR, CRp or cytogenetic response. In the cytarabine plus AS1411 group, 3/13 (23%) patients showed responses to treatment, with one CR, one CRp and one cytogenetic response. Three patients from the cytarabinealone group who failed to achieve remission with cytarabine alone crossed over to receive AS1411 plus cytarabine, one of whom experienced a 90% reduction in leukemic blast count. Conclusion: The combination of AS1411 at 10 mg/kg/day for 7 days with high-dose cytarabine 3,000 mg/m2/day over 4 days appeared to be well tolerated and showed signs of activity in patients with relapsed/refractory AML. Further patients are now being randomized to cytarabine or cytarabine plus the higher dose of 40 mg/kg/day AS1411.

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

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3104-3104 ◽  
Author(s):  
Sung H Hong ◽  
David S Siegel ◽  
Michele L Donato ◽  
David H. Vesole ◽  
Andrew L Pecora ◽  
...  
Keyword(s):  
Phase I ◽  
Disease Progression ◽  
Board Of Directors ◽  
Phase Ii ◽  
Dose Escalation ◽  
Synergistic Effects ◽  
Phase Iii ◽  
High Dose ◽  
Combination Regimen ◽  
Advisory Committees

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

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