A Phase II Expansion Study Of Vorinostat In Combination With Idarubicin and Cytarabine For Patients With Acute Myelogenous Leukemia (AML) With FLT3 Molecular Alterations

Abstract Background The combination of vorinostat, idarubicin and cytarabine (IA+vorinostat) is associated with high response rate in patients with newly diagnosed acute myelogenous leukemia (AML) or higher-risk myelodysplastic syndromes (MDS) (JCO 2012;30:2204). In that study, presence of FLT3-ITD was associated with 100% overall response rate (ORR) in 11 patients. To confirm the efficacy of this combination, we extended the phase II study to treat 2 additional cohorts: one for patients with newly diagnosed (untreated cohort) and the other with relapsed and refractory (R/R cohort) AML or higher-risk MDS with FLT3 alteration (both ITD and D835 mutation). Methods Patients with the above diagnosis, ages 15 to 65 years, with appropriate organ function (measured cardiac ejection fraction ≥ 50%, serum creatinine ≤ 2 mg/dl, total bilirubin ≤ 2 mg/dl, and GPT/GOT ≤ 2.5 x upper limit of normal) whose eastern cooperative group (ECOG) defined performance status ≤ 2 were eligible for the study. Study treatment comprised of vorinostat 500 mg orally three times a day (days 1 to 3), idarubicin 12 mg/m2 intravenously (IV) daily x 3 days (days 4 to 6), and cytarabine 1.5 g/m2 IV as a continuous infusion daily x 3 - 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy with lower dose combination and up to 12 months of maintenance therapy with single-agent vorinostat. Result Untreated cohort included 26 patients, whereas 13 patients were treated in R/R cohort (total 39 patients). Thirty six patients had de novo AML, 1 had de novo MDS and 2 had therapy-related AML. For the R/R patients, the median number of prior therapies was 3 (range: 1-6). The median age of the entire study group was 49 (range: 19-64) and 17 (44%) were male. Among the patients whose cytogenetic result were available, 20 (51%) patients had normal and 15 (39%) had abnormal karyotype. By Medical Research Council (MRC) criteria, 30 (77%) patients had intermediate risk and 9 (23%) had poor risk karyotype. Thirty three (85%) patients had FLT3-ITD only, 4 (10%) had both FLT3-ITD and D835 mutation, and 2 (5%) had D835 mutation only. Seventeen (44%) patients had NPM1 mutation. In untreated cohort (N = 26), CR and CRp were documented in 21 (80%) and 2 (8%) patients, respectively (ORR = 88%). In R/R cohort (N = 13), overall response (OR) was observed in 4 (30%) patients (CR in 2 [15%] and CRp in 2[15%]). Of those 4 patients who had OR in R/R cohort, 2 patients were refractory to other high-dose cytarabine-based regimen. The median duration of CR or CRp was 9.2 months (range: 0.1-48.4) in untreated cohort and was 2.9 months (range: 1.6-4.7) in R/R cohort. Twelve (46%) patients in the untreated cohort were bridged to stem cell transplant (SCT) while they were in 1st CR. None of the patients in R/R cohort were bridged to SCT. No difference in response was observed in 1) younger (Age < 60) vs. older patients, 2) normal vs. abnormal karyotype, 3) intermediate vs. poor risk cytogenetics by MRC criteria, 4) presence of RAS mutation, 5) presence of NPM1 mutation, or 6) de novo vs. therapy-related disease. The median overall survival (OS) was 21.7 months (95% CI: 8.1-35.3) in the untreated cohort and was 4.9 months (95% CI: 0.1-10.4) in the R/R cohort. Early treatment related mortality (defined by the death within 4 weeks of the induction) was documented in 1 (4%) patient in the untreated cohort and 2 (15%) patients in the R/R cohort. Toxicity profiles were similar to that reported in the original phase II study (JCO 2012;30:2204). Discussion Vorinostat in combination with IA provides high response rate and durable remission in previously untreateed AML or higher risk MDS patients with FLT3 alteration but is less effective in patients with R/R disease. Phase III randomized study of IA+/- vorinostat in previously untreated AML patients is ongoing (SWOG S1203). Disclosures: Off Label Use: vorinostat in MDS and AML. Cortes:Ambit: Research Funding; Astellas: Research Funding; Argo: Research Funding; Novartis: Research Funding.

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A Phase II study of VNP40101M in elderly patients (pts) with de novo poor risk acute myelogenous leukemia (AML)

Journal of Clinical Oncology ◽

10.1200/jco.2008.26.15_suppl.7026 ◽

2008 ◽

Vol 26 (15_suppl) ◽

pp. 7026-7026 ◽

Cited By ~ 2

Author(s):

G. J. Schiller ◽

D. DeAngelo ◽

N. Vey ◽

S. Solomon ◽

R. Stuart ◽

...

Keyword(s):

Elderly Patients ◽

Phase Ii ◽

Acute Myelogenous Leukemia ◽

De Novo ◽

Phase Ii Study ◽

Myelogenous Leukemia ◽

Poor Risk ◽

Acute Myelogenous

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A Phase II Study of Sequential Decitabine and Rapamycin in Acute Myelogenous Leukemia

Leukemia Research ◽

10.1016/j.leukres.2021.106749 ◽

2021 ◽

pp. 106749

Author(s):

Jane L. Liesveld ◽

Andrea Baran ◽

Mitra Azadniv ◽

Haley Misch ◽

Katherine Nedrow ◽

...

Keyword(s):

Phase Ii ◽

Acute Myelogenous Leukemia ◽

Phase Ii Study ◽

Myelogenous Leukemia ◽

Acute Myelogenous

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A Phase II Study of Midostaurin and 5-Azacitidine for Untreated Elderly and Unfit Patients With FLT3 Wild-type Acute Myelogenous Leukemia

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2019.10.018 ◽

2020 ◽

Vol 20 (4) ◽

pp. 226-233.e1

Author(s):

Benjamin K. Tomlinson ◽

Molly M. Gallogly ◽

Donna M. Kane ◽

Leland Metheny ◽

Hillard M. Lazarus ◽

...

Keyword(s):

Phase Ii ◽

Acute Myelogenous Leukemia ◽

Phase Ii Study ◽

Myelogenous Leukemia ◽

Wild Type ◽

Acute Myelogenous ◽

Unfit Patients

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Phase II study of low-dose continuous infusion homoharringtonine in refractory acute myelogenous leukemia

Cancer ◽

10.1002/1097-0142(19890301)63:5<813::aid-cncr2820630502>3.0.co;2-v ◽

1989 ◽

Vol 63 (5) ◽

pp. 813-817 ◽

Cited By ~ 36

Author(s):

Hagop M. Kantarjian ◽

Michael J. Keating ◽

Ronald S. Walters ◽

Charles A. Koller ◽

Kenneth B. McCredie ◽

...

Keyword(s):

Continuous Infusion ◽

Phase Ii ◽

Acute Myelogenous Leukemia ◽

Low Dose ◽

Phase Ii Study ◽

Myelogenous Leukemia ◽

Acute Myelogenous

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The VcR-CVAD Regimen Produces a High Complete Response Rate in Untreated Mantle Cell Lymphoma (MCL): First Analysis of E1405 – A Phase II Study of VcR-CVAD with Maintenance Rituximab for MCL.

Blood ◽

10.1182/blood.v114.22.1661.1661 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1661-1661 ◽

Cited By ~ 6

Author(s):

Brad S Kahl ◽

Hailun Li ◽

Mitchell R Smith ◽

Randy D. Gascoyne ◽

Elisabeth Paietta ◽

...

Keyword(s):

Phase Ii ◽

Research Funding ◽

Response Rate ◽

Complete Response Rate ◽

Phase Ii Study ◽

Cell Lymphoma ◽

Complete Response ◽

Mantle Cell ◽

Grade 3

Abstract Abstract 1661 Poster Board I-687 Introduction One approach to improving outcomes in Mantle Cell Lymphoma (MCL) is to incorporate newer targeted agents into standard chemotherapy regimens. As the proteasome inhibitor bortezomib (Velcade‘) achieved a 33% response rate in relapsed MCL, we hypothesized that the incorporation of Velcade (Vc) into a modified R-hyperCVAD chemotherapy backbone would result in a high complete response rate (CR). The new regimen, VcR-CVAD, was tested for safety and efficacy in a phase II study within the Wisconsin Oncology Network (UW) and demonstrated a CR rate of 77% (Kahl, ASH 2008). To determine the safety and efficacy of this regimen in a cooperative group setting, we initiated E1405: a phase II study of VcR-CVAD with maintenance rituximab (MR) for untreated MCL. Methods Eligible patients had histologically confirmed, previously untreated MCL, PS 0-2, and adequate end organ function. The treatment plan included: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1-3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1-2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1-4. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF support. Patients achieving SD, PR, or CR received MR administered as 4 weekly treatments every 6 months for 2 years (protocol therapy). Patients had an option to receive high dose chemotherapy and autologous stem cell transplantation (off protocol) rather than MR. The primary endpoint of the trial was the CR rate, incorporating PET imaging, to VcR-CVAD induction therapy. Results Seventy-six eligible patients were enrolled between 5/07 and 10/08. Baseline characteristics include median age 62 (40-76), 59M:17F, 91% stage III/IV, and 39% with elevated LDH. Sixty-four patients (84%) completed VcR-CVAD induction therapy. Reasons for treatment discontinuation included PD (1), toxicity (4), patient preference (2), and other/unknown (5). Response information is available on 74 patients while data is outstanding on 2 patients. The ORR was 96% (73/76; 95% CI, 89%-99%), CR rate 75% (57/76; 95% CI, 64%-84%) and the PR rate 21% (16/76; 95% CI, 13%-32%). Six of the PR patients were coded as such because of protocol violations in which a post-treatment bone marrow biopsy or PET scan was not obtained. The CR rate in the 68 completely restaged patients was 84%. Forty-four patients proceeded to planned MR while 21 patients went off protocol to SCT consolidation. Median follow up is currently too short (9 months) to assess PFS and OS. The major toxicity of the treatment regimen was expected myelosuppression. Grade 3-4 non hematologic toxicities were rare. No patients developed grade 3-4 neuropathy. There were no treatment related deaths. Conclusion The VcR-CVAD induction produced high overall response (96%) and CR rate (75%) in a representative MCL patient population treated on a cooperative group protocol. The CR rate was high and comparable to the UW pilot study (77%). No episodes of severe painful peripheral neuropathy were reported using the reduced vincristine dosage and the overall toxicity profile was very acceptable. Longer follow up is needed to determine if the high CR rate will translate into improved PFS and OS. Disclosures Kahl: Genentech: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Off Label Use: Bortezomib as front line treatment in MCL. Smith:Genentech: Research Funding; Millennium: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding. Horning:Genentech: Honoraria, Research Funding.

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Interim Analysis of Phase II Study of the Bortezomib-Melphalan-Prednisolone Induction Therapy Followed By Lenalidomide-Plus-Dexamethasone Consolidation and Lenalidomide Maintenance in Non-Transplant Eligible Patients with Newly Diagnosed Symptomatic Multiple Myeloma.

Blood ◽

10.1182/blood.v126.23.3043.3043 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3043-3043

Author(s):

Tadao Ishida ◽

Hideo Kimura ◽

Koumei Kubo ◽

Kazutaka Sunami ◽

Shuji Ozaki ◽

...

Keyword(s):

Phase Ii ◽

Induction Therapy ◽

Research Funding ◽

Response Rate ◽

Phase Ii Study ◽

Staging System ◽

Best Response ◽

Need To Evaluate ◽

Treatment Number ◽

Reduced Intensity

Abstract Background In Japan, the phase II study of bortezomib-melphalan-prednisolone (VMP) for NDMM using the same protocol of VISTA trial revealed that there were more treatment discontinuation in this study than in the VISTA study. We planned five cycles of reduced intensity VMP therapy as an induction. And it is reported that lenalidomide plus low dose dexamethasone (Rd) therapy is very effective regimen after VMP therapy. In order to further improve its outcome, patients are treated with six cycles of Rd and maintenance of lenalidomide after VMP induction. Patients and methods We included 82 pts with NDMM. Pts were received 5 cycles of VMP followed by 6 cycles of Rd. After Rd, pts received maintenance of lenalidomide. VMP included the IV or SQ administration of weekly bortezomib at 1.3 mg/m2 in combination with oral melphalan 6 mg/m2 and prednisone 60 mg/m2 once daily on days 1-4 of a 35-day cycle. Rd treatment consisted of lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly of a 28-day cycle. Lenalidomide maintenance therapy consisted of lenalidomide 10 mg daily on days 1-21 of a 28-day cycle. Results In total, 82 pts were recruited in the trial by 27 Japanese centers between 10/2012 and 8/2014. Median age were 73.5 years (range 61-84), 37.8% were 75 years of age or older, 45.1% were male, 48.8% had International Staging System (ISS) stage II and 20.7% had ISS stage III. Fifty four patients had IgG-type myeloma (65.8%), 19 had IgA-type (23.2%), and 9 had Bence Jones-type (11%). Of the cases analyzed by FISH (N=80), 16.3% had t(4;14), 10% had del 17p and 41.3% had +1q21. Eight patients (10%) had t(4;14) and +1q21, five patients (6.3%) had del 17p and +1q21 and only one patient (1.3%) had t(4;14), del 17p and +1q21. The best response during VMP therapy (the maximum treatment number was 5 cycles) could be evaluated. After five course of VMP therapy, the rates of partial response (PR) or better were 68% including sCR (5%), CR (6%),VGPR (20%) and PR (37%). The best response rate after VMP+Rd (maximum treatment number of Rd was 6 cycles) was also evaluated. The rates of PR or better were 90% including sCR (6%), CR (16%), VGPR (39%) and PR (29%). The most commonly observed grade 3 or higher adverse events during VMP therapy were anemia (30%), neutropenia (16%), thrombocytopenia (5%) and GI toxicity (6%). Summary The induction therapy of reduced intensity VMP was safe and effective. The best response rate after VMP+Rd was very effective. However, we need to evaluate consolidation of Rd and maintenance of lenalidomide after longer follow up. Disclosures Ishida: Takeda: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria. Sunami:Ono: Research Funding; Takeda: Research Funding.

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An Open-Label Phase II Trial of the Combination of Decitabine, SQ Bortezomib and Pegylated Liposomal Doxorubicin for the Treatment of Patients with Relapsed/Refractory Acute Myelogenous Leukemia

Blood ◽

10.1182/blood-2021-147349 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2352-2352

Author(s):

Laura A. Potter ◽

Maria Galkin ◽

Aaron S. Rosenberg ◽

Rasmus T. Hoeg ◽

Mehrdad Abedi ◽

...

Keyword(s):

Bone Marrow ◽

Phase Ii ◽

Research Funding ◽

Liposomal Doxorubicin ◽

Phase Ii Trial ◽

Pegylated Liposomal Doxorubicin ◽

Myelogenous Leukemia ◽

Additional Patient ◽

Npm1 Mutation ◽

Prior Therapy

Abstract Background Relapsed/refractory (R/R) acute myeloid leukemia (AML) remains a challenge to cure. Prior studies of hypomethylating agent (HMA) decitabine (DEC), proteasome inhibitor bortezomib (BTZ), and anthracycline (AC) pegylated liposomal doxorubicin (PLD) monotherapy, as well as DEC + BTZ and BTZ + PLD regimens, have demonstrated safety and modest activity in R/R AML. Inhibition of NF-κB signaling by BTZ and DEC could prevent AC resistance resulting from NF-κB activity. Thus, we hypothesized that the DEC + BTZ + PLD (DBP) regimen would have activity in R/R AML. Methods We performed a phase II trial of DBP, with a safety lead-in cohort, in patients aged 18-90 with R/R AML. The original protocol called for 1-4 28-day (D) cycles of induction with intravenous (IV) DEC 20mg/m 2 on D1-10, subcutaneous (SQ) BTZ 1.3mg/m 2 on D1, 4, 8, and 11, and IV PLD 40mg/m 2 on D4. Dose-limiting toxicity (DLT) of grade 3 peripheral neuropathy (G3 PN) in the first 2 patients led to a revised schedule of BTZ on D5, 8, 12, and 15 and PLD on D12, eliminating simultaneous DBP dosing on any 1 day. Patients achieving a bone marrow blast count <5% after any course of induction proceeded to the continuation regimen: 28-D cycles of DEC on D1-5, BTZ on D1 and 8, and PLD on D12. Treatment continued until progression, intolerance, bone marrow transplant (BMT), study withdrawal, or administration of 12 cycles. Patients reaching lifetime maximum AC exposure could remain on trial with PLD removed from their regimen. Primary endpoint was objective response rate (ORR), defined as complete remission (CR) + CR with incomplete hematological recovery (CRi) + partial remission. Response was based on International Working Group criteria and determined by blood count values between cycles. Secondary endpoints of overall and event-free survival (OS, EFS) were estimated by Kaplan-Meier method. Toxicity was monitored per Common Terminology Criteria for Adverse Events (AEs) v4.03. Results Ten patients were enrolled from May 2016 to February 2018, after which the sponsor closed the protocol. Median age was 57 years [range 27-69]. Patients were 50% female, 60% White, 10% African American/Black, 30% other/mixed race, and 40% Hispanic/Latino, with median baseline ECOG score of 1 [0-1] and median 2 [1-3] lines of prior therapy. Sixty percent had de novo and 40% had secondary disease. By WHO subtype, 30% had AML with MRC, 20% NPM1 mutation, 10% inv(3), 10% therapy-related, and 30% not otherwise specified. European LeukemiaNet 2017 risk was favorable in 20%, intermediate in 40%, and adverse in 40%. Median number of cycles completed was 2 [1-7] with a median time on study of 100.5 days [35-678]. One patient achieved CR and 2 achieved CRi for an ORR of 30%. An additional patient likely had a CR with <5% blasts and count recovery but had a suboptimal aspirate differential. Including this unconfirmed CR, ORR was 40%. An additional 2 (20%) achieved morphological leukemia-free state (MLFS). Of the 6 patients with any response (CR + CRi + MLFS), 2 achieved best response after cycle 1, 2 after cycle 2, 1 after cycle 3, and 1 after cycle 4. Relapse occurred in 2 of 5 (40%) while on study, at 425 days after CRi and 83 days after MLFS. All 3 patients with prior HMA exposure were non-responders. All patients discontinued treatment. Reasons included BMT (40%), AE (30%), progression (20%) and insurance loss (10%). Half planned to bridge to BMT as next-line therapy following study treatment. When taken off study, 50% were alive while 20% had died from AML complications, 20% from graft-versus-host-disease post-BMT, and 10% after relapse post-BMT. Median OS was 6.67 months (95% confidence interval [CI] 6.07 to not reached [NR]). Median EFS was 3.22 months (95% CI 1.50 to NR), with a maximum EFS of 16.93 months. Following G3 PN in the first 2 patients, no DLTs occurred on the modified regimen. Seventy percent of patients experienced at least possibly related G3+ AEs or serious AEs (SAEs). Of the 22 related G3+ AEs, anemia and decreased platelet count were seen in 50% and dizziness in 20%. Of the 22 related SAEs, anorexia, fatigue, PN, febrile neutropenia, and bacteremia were most common, each occurring in 20%. Conclusion The DBP triplet demonstrated preliminary anti-AML activity in a R/R AML patient cohort. Staggered dosing was better tolerated than simultaneous DBP. DBP may serve as an effective bridge to BMT for some patients. This study supports further evaluation of DBP, or related combinations, in R/R AML. Disclosures Rosenberg: Takeda, Janssen: Speakers Bureau. Abedi: Seattle Genetics: Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Speakers Bureau. Tuscano: BMS, Seattle Genetics, Takeda, Achrotech, Genentech, Pharmacyclics, Abbvie: Research Funding. Jonas: AbbVie, BMS, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Treadwell: Consultancy; 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, Treadwell: Research Funding; AbbVie: Other: Travel reimbursement. OffLabel Disclosure: Bortezomib is FDA-approved for the treatment of multiple myeloma in patients who have already been treated with 2 lines of prior therapy and progressed on the most recent therapy. Decitabine is indicated for treatment of patients with myelodysplastic syndromes. Doxorubicin is approved in AML among other cancers.

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An early phase II study of CPT-11: a new derivative of camptothecin, for the treatment of leukemia and lymphoma.

Journal of Clinical Oncology ◽

10.1200/jco.1990.8.11.1907 ◽

1990 ◽

Vol 8 (11) ◽

pp. 1907-1912 ◽

Cited By ~ 145

Author(s):

R Ohno ◽

K Okada ◽

T Masaoka ◽

A Kuramoto ◽

T Arima ◽

...

Keyword(s):

Acute Leukemia ◽

Phase Ii ◽

Early Phase ◽

Topoisomerase I ◽

Phase Ii Study ◽

Lymphoblastic Leukemia ◽

Myelogenous Leukemia ◽

Cross Resistance ◽

Treatment Schedule ◽

Acute Myelogenous

An early phase II study of a new camptothecin analog and an inhibitor of topoisomerase I, CPT-11, was conducted in 62 patients with refractory leukemia and lymphoma by four different treatment schedules in a multiinstitutional cooperative study. CPT-11 therapy resulted in four complete remissions (CRs) and three partial remissions (PRs) in 29 assessable non-Hodgkin's lymphoma (NHL) patients, one PR in three Hodgkin's disease (HD), one CR and one PR in 11 acute lymphoblastic leukemia (ALL), and one PR in 15 acute myelogenous leukemia (AML) patients. Single infusion of 200 mg/m2 every 3 to 4 weeks produced no response in both leukemia and lymphoma patients. Sixty-minute infusions of 40 mg/m2/d for 5 days every 3 to 4 weeks or for 3 days weekly produced four CRs (17%) and four PRs (17%) in 24 patients with malignant lymphoma. Sixty-minute infusions of 20 mg/m2 twice a day for 7 days every 3 to 4 weeks resulted in one CR and two PRs in 12 patients with acute leukemia. No response was seen in an acute leukemia patient by another treatment schedule. CPT-11 was effective in two (15%) of 13 primarily refractory leukemia and lymphoma cases, in two of four relapsed cases, and in seven (17%) of 41 relapsed and refractory cases. Major side effects were leukopenia (91%) and gastrointestinal (GI) (76%). CPT-11 was shown to be effective against refractory leukemia and lymphoma, and thus deserves further clinical study; the novel antitumor activity mode of this drug predicts no cross-resistance to presently available antitumor drugs.

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