A Phase I/II Trial of Ixazomib (Ix), Pomalidomide (POM), and Dexamethasone (DEX), in Relapsed/Refractory (R/R) Multiple Myeloma (MM) Patients: Responses in Double/Triple Refractory Myeloma and Poor Risk Cytogenetics

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3316-3316 ◽  
Author(s):  
Amrita Krishnan ◽  
Prashant Kapoor ◽  
Joycelynne Palmer ◽  
Ni-Chun Tsai ◽  
Shaji Kumar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Phase I ◽  
Research Funding ◽  
Standard Dose ◽  
Single Agent ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Refractory Disease ◽  
Poor Risk

Abstract Triplet regimens combining an immunomodulatory agent, a proteasome inhibitor (PI), and a steroid are used to treat newly diagnosed and relapsed multiple myeloma (MM). Although ixazomib (Ix), an oral PI with single agent activity, can be combined with lenalidomide (LEN), patients (pts) with relapsed/refractory (R/R) MM are often LEN-refractory. Pomalidomide (POM) has single agent activity in LEN-refractory disease, and both POM and Ix also show activity in poor cytogenetic risk pts. Methods: Primary objectives: 1) determine the maximum tolerated dose (MTD) of Ix in combination with standard dose POM and dexamethasone (DEX), and 2) evaluate the anti-tumor activity of the triplet. The treatment regimen included two dose levels (3 mg and 4 mg) of Ix on days 1, 8, 15; POM 4 mg days 1-21; and DEX 40 mg days 1, 8, 15, 22, of a 28 day cycle. Eligibility: R/R MM after >1 prior therapy, LEN-refractory, and ≤ grade(gr) 1 peripheral neuropathy (PN). Pts were treated until progression or unacceptable toxicity. Design: Phase I study utilizing a standard 3+3 design; dose limiting toxicities (DLTs) defined during cycle 1. Results: 32 pts treated, 31 evaluable for toxicity and response. Pts received a median 4 cycles (range 1-13); median follow-up is 5.5 months (range 1.8-21.1). Six pts treated on DL1, 25 treated on DL2, the MTD/Phase II dose (P2D). Median age: 62 years (range 38-84); median time from diagnosis: 3.7 years (range 1.0-8.9); median number prior therapies: 3 (range 1-5); prior transplant: n = 23 (74%); double (LEN/Bortezomib[BOR]) or triple (LEN/BOR/Carfilzomib[CFZ]) refractory: 19 (61%). Phase I: DL1 expanded to n=6 after 1/3 pts experienced DLT (gr3 lung infection); no further DLT seen on DL 1 or 2. Adverse events (AEs) related to POM and/or Ix: ANC decrease Gr1/2 n=11 (35%), Gr3/4 n=10 (32%), platelet decrease Gr1/2 n=9 (29%), lymphocyte decrease Gr1/2 n=8 (26%), Gr3/4 n=11 (35%), PN Gr1/2 n=9 (29%), no Gr3/4. Response: Phase I and II, n=31 pts treated. ORR: 45% (6 VGPR, 8 PR); Clinical Benefit Rate (CBR): 81% (6 VGPR, 8 PR, 3 MR, 8 SD). In the pts with high risk cytogenetics (7[23%] 1q, 3[10%] 17p, 2[6%] t(4;14)) an ORR of 58% (3 VGPR, 4 PR) was seen, and the CBR was 83%. In the double or triple refractory pts, an ORR of 26% and CBR of 79% (1 VGPR, 4 PR, 3 MR, 7 SD) were observed. Conclusions: Ix/POM/DEX is a well-tolerated oral combination therapy, and responses were seen even at DL1 and in high risk patients, including those with poor-risk cytogenetics or advanced refractory disease. Disclosures Kapoor: Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Kumar:Millennium: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy; Onyx: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding. Lonial:Novartis: Consultancy; BMS: Consultancy; Janssen: Consultancy; Merck: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy; Millenium: Consultancy; Janssen: Consultancy; Onyx: Consultancy. Nathwani:Carevive Systems, Inc.: Research Funding. Forman:Mustang Therpapeutics: Other: Construct licensed by City of Hope. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding.

Final Report of GFM-VOR2007 Study: a Phase I/II Study of Vorinostat and Low Dose Cytarabine (LDAC) for MDS Patients with Azacitidine (AZA) Failure

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3825-3825 ◽  
Author(s):  
Thomas Prebet ◽  
Thorsten Braun ◽  
Odile Beyne-Rauzy ◽  
Eric Wattel ◽  
Francois Dreyfus ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Research Funding ◽  
Response Rate ◽  
Single Agent ◽  
Therapeutic Index ◽  
Median Number ◽  
Clinical Activity ◽  
Final Report ◽  
Sequential Administration

Abstract Abstract 3825 INTRODUCTION: AZA is the standard of care for patients (pts) treated for high risk MDS. Outcome of patients with AZA failure is poor with no standard treatment currently available (Prebet, JCO, 2012), and alternative strategies are required for this population. Vorinostat is a histone deacetylase inhibitor with clinical activity in MDS and leukemia, although response rate remains low when used as single agent (Garcia-Manero Blood 2008). By contrast, combinations with cytotoxic or targeted therapies seem promising. METHODS: In this study (clinicaltrials.gov NCT00776503), we combined LDAC (10mg/m2/d in the first cycle, then 20 mg/m2/d) for 14 days SC every 28 day cycle and escalating doses of vorinostat. Two schedules of vorinostat, (400mg/day orally) beginning on day 1 (arm A) or on day 14 (arm B), were tested in 3 cohorts receiving escalating treatment duration (7days, 10 days and 14 days per cycle) with a classical 3+3 phase I schedule. 7 additional pts were included at the dose level recommended by the DSMB for each cohort (arm A and B). Inclusion criteria were age >18, MDS or AML with 20–30% blasts, IPSS≥1.5, prior failure of AZA. Toxicity was assessed using CTCAE V3. Patients with clinical benefit could continue on therapy after cycle 3 until progression. RESULTS: A total of 42 pts were included and 40 were treated, 23 pts in arm A and 17 pts in arm B. 2 pts died before the beginning of treatment. Median age was 74 years (range 46– 88), median number of previous treatments was 2 (1–3), and median number of cycles of previous AZA treatment was 11 (range 1–25). All pts were IPSS Int-2 (n=21) or High risk MDS (n=19). A total of 137 cycles of treatment was administered with a median number of 3 cycles/pt and 11 pts received more than 3 cycles (28%). The recommended dose was determined for arm A at 10 days of vorinostat and for arm B at 14 days. During cycle 1, dose limiting toxicities were grade 3 fatigue (n=2), grade 4 bilirubin (n=1), and grade 4 infection (n=2), all in arm A. The most frequent non-limiting toxicities were myelosuppression (37/40), infections (8/40) moderate fatigue (23/40) and mild GI toxicities (25/40). Response was centrally reviewed according to IWG 2006 criteria. Overall response rate was 17% in 35 evaluable pts including 2 CRi, 2 HI and 2 marrow CR. Median duration of response of 3 months (range [2–6+]). There were 2 responders in arm A (1 in the 7 day cohort and 1 in the 14 day cohort) and 4 responders in arm B (1 in the 7 day cohort, 2 in the 10 day cohort, 1 in the 14 day cohort) including the 2 CRi. 18 pts remained stable without HI and 11 progressed during treatment. Median overall survival of the cohort was 9.2 months and 1-year probability of survival was 36%. CONCLUSIONS: Our results show that 400 mg/day vorinostat can be combined to LDAC and given for 10 days (arm A) to 14 days (arm B) with acceptable side effects. It also suggests that the sequential administration might be associated with an increased therapeutic index since longer vorinostat therapy duration could be tolerated. Response rate remains modest but survival compared favorably with conventional care in this group of patients with dismal outcome. Disclosures: Fenaux: Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1168-1171 ◽  
Author(s):  
Maurizio Zangari ◽  
Eric Siegel ◽  
Bart Barlogie ◽  
Elias Anaissie ◽  
Fariba Saghafifar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Multivariate Analysis ◽  
High Risk ◽  
Doppler Ultrasonography ◽  
Standard Dose ◽  
Single Agent ◽  
Cytotoxic Chemotherapy ◽  
Newly Diagnosed ◽  
Statistical Association ◽  
Increased Risk

Ten percent of newly diagnosed myeloma patients treated with any type of chemotherapy develop deep venous thrombosis (DVT). Thalidomide has proven activity in refractory multiple myeloma (MM), and although single-agent thalidomide has minimal prothrombogenic activity, its combination with cytotoxic chemotherapy is associated with a significantly increased risk of DVT. We analyzed the incidence of DVT in 232 MM patients who received a combination of chemotherapy and thalidomide on 2 protocols that differed only by the inclusion of doxorubicin in one. DT-PACE (dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophos- phanide/etoposide) was offered to patients with preceding standard dose therapy, but no prior autotransplantation, while DCEP-T (dexamethasone/cyclophosphamide/etoposide/cisplatin/thalidomide) was administered for relapse after transplantation. If there were signs or symptoms suggestive of DVT, patients received additional investigations, including Doppler ultrasonography, followed by venography if indicated. Only patients on DT-PACE but not DCEP-T experienced an increased incidence of DVT. A statistical association between the incidence of DVT and combination chemotherapy including doxorubicin (P = .02) was observed; this association was confirmed on multivariate analysis. MM patients treated with thalidomide and doxorubicin have a high risk of developing DVT.

A Phase I/II Study of Bortezomib and Low Dose Intravenous Melphalan (BM) for Relapsed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2555-2555 ◽  
Author(s):  
Rakesh Popat ◽  
Heather E. Oakervee ◽  
Nicola Foot ◽  
Samir Agrawal ◽  
Patricia Smith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Progressive Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Median Number ◽  
Overall Response ◽  
Grade 3 ◽  
Number Of Cycles

Abstract Background: Bortezomib as a single agent has known efficacy in the treatment of relapsed multiple myeloma. The overall response rate (CR+PR+MR) was 35% in the SUMMIT study and 46% in the APEX study. In-vitro studies including our own have demonstrated potent synergy with other chemotherapeutic agents such as melphalan. It therefore follows that responses to bortezomib may be further improved by the combination of such drugs. Aims: The primary objectives of this Phase I/II study was to assess the safety, tolerability and response rates in patients with relapsed multiple myeloma; secondary objectives being time to progression (TTP) and overall surival (OS). Methods: This was a multi-centre, non-randomised trial for patients with relapsed myeloma. Patients received bortezomib 1.3mg/m2 on days 1,4,8 and 11 of each 28 day cycle with melphalan on day 2 at increasing dose levels. This was initially at 10mg/m2, but due to cytopenias subsequently at 2.5 and 5mg/m2 (levels 1a, 1 and 2) and we plan to escalate to 7.5mg/m2. Up to 8 cycles were given with dexamethasone added for stable or progressive disease after 4 or 2 cycles respectively. Responses were determined by EBMT criteria. Results: To date, 18 patients have been enrolled (12 male 6 female; median age 60 [range 44–73]; median number of prior therapies 3 [range 1–5] of which 17 have had at least one autologous stem cell procedure with high dose melphalan; 10 prior thalidomide and 2 prior bortezomib). 12 patients received melphalan at 10mg/m2 but due to unacceptable delays predominantly due to thrombocytopaenia, subsequent treatment levels commenced at 2.5mg/m2. The median number of cycles completed thus far is 4 (range 0–8) and of the 16 evaluable, the overall response rate (CR+PR+MR) across all treatment levels was 50% rising to 75% following the addition of dexamethasone as per protocol. At level 1a (melphalan 10mg/m2 ,N=12, median number of cycles completed =5) the best responses (with dexamethasone as indicated) were: 1CR, 1 VGPR, 5 PR, 2 MR; at level 1 (melphalan 2.5mg/m2, N=4) 1 PR, 2 MR (after 2 cycles only). The median time to any response was 1 cycle (range 1–3 ). Three patients have progressive disease, but the median TTP and OS have not yet been reached (median follow-up 3 months). Non-haematological toxicities have been modest with 7 SAEs reported of which only 1 was possibly drug related (myocardial infarction), and 4 episodes of Grade 3 neuropathy (2 resulting in study withdrawal). The commonest grade 3–4 haematological toxicity was thrombocytopaenia (N=10) complicated by bleeding in one patient, followed by neutropenia (N=6). Summary: The combination of bortezomib and intravenous melphalan can be given safely to patients with relapsed multiple myeloma and dose escalation is ongoing. Myelosupression was the commonest grade 3–4 adverse event. A response rate of 50% was seen, which was further improved to 75% with the addition of dexamethasone. This combination may therefore result in higher responses than single agent bortezomib in heavily pretreated patients.

The Tolerability of Combination Therapy with Thalidomide and 5-Azacitidine in Patients with Advanced Myelodysplastic Syndromes (MDS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1749-1749 ◽  
Author(s):  
Melita K Kenealy ◽  
John F Seymour ◽  
Cowan Linda ◽  
Alvin Milner ◽  
Pratyush Giri ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Standard Dose ◽  
Performance Status ◽  
Single Agent ◽  
Median Number ◽  
Respiratory Disorder ◽  
Advisory Committees ◽  
Impaired Performance

Abstract Abstract 1749 Poster Board I-775 Introduction Both thalidomide (Thal) and 5-azacitidine (Vidaza; AZA) have single-agent activity in patients (pts) with myelodysplastic syndromes (MDS), but there is limited experience with the combination. The addition of Thal to AZA may improve efficacy, but tolerability of the combination may be limited by side-effects. Patients and Methods This analysis included all evaluable pts on the Ph I/II Australasian Leukaemia and Lymphoma group (ALLG) MDS3 study of Thal and AZA. Pts were eligible if they had any FAB subtype of MDS; those with RA and RARS also required clinically significant cytopenias. Pts were excluded if they had previously received Thal or its derivatives or any demethylating agent. All pts were treated with Thal 50mg/d for the first 28d increasing to 100mg/d for a max of 12 Mo treatment and AZA 75mg/m2/d x7d every 28d until progression or prohibitive toxicity. The protocol specified dose delays or reductions for treatment-related toxicities. Results A total of 80 pts have been enrolled, with 41 treated between 7/08 – 7/09 currently evaluable. Median age is 68.5y (42-81) with 66% male. FAB MDS category was RA 15%, RARS 10%, RAEB 46%, RAEB-t 10% and CMML 17% with IPSS low 12%, intermed-1 37%, intermed-2 34% and high 12%. Median baseline Hb 88g/L (71-127), ANC 1.91×10 9/L (0.06-87.65) and platelets 75 ×10 9/L (10-399). Median time post diagnosis was 9 Mo. Seventeen pts (41%) remain on treatment with AZA alone (n=3) or both agents (n=14) with a median follow-up of 208d (60-297d). For those still on Thal and AZA median exposure to Thal is 209d (60-297d), with a median 7 cycles of AZA (2-9). For those 27 ceased Thal median exposure was 49d (17-220d) and of 24 ceasing AZA, median number cycles was 2 (1-8). Of 27 pts ceasing one (n=3) or both (n=24) agents; 7 withdrew consent, 3 at investigator decision, 4 for toxicity, 6 progressive disease, 1 lack of efficacy, 2 death (1 respiratory failure in setting of PD and WCC>300, 1 sepsis) and 4 unknown. There were 3 additional deaths within 28d of ceasing study therapy (all with PD); 2 due to sepsis and 1 intracranial haemorrhage. No pt experienced peripheral neuropathy Gr3 or worse. During cycle 1 of the first 40 consecutive patients on treatment, there were 18 episodes of Gr3+ non-haematologic toxicity in 13 patients; this was more likely in those with ECOG 2 (67% v 26%, p=0.053), age>65y (39% v 19%, p=0.175) and baseline ANC'0.5 (75% v 21%, p=0.008). Most of these events were infection related (a recognised risk of underlying MDS and of AZA alone); others occurred on only one occasion each (syncope, postop hemorrhage, respiratory disorder, renal failure, abdominal pain, pain, thrombosis and hypokalemia). Conclusions The combination of Thal 50-100mg/d and standard dose AZA is feasible without unexpected toxicity. Infections are common in the first cycle, particularly in pts with baseline neutropenia or impaired performance status. An updated toxicity analysis will be presented. Disclosures Kenealy: Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Seymour:Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mills:Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Szer:Celgene Pty Ltd: Honoraria, Speakers Bureau.

scholarly journals Combination Thioguanine and Decitabine Is Highly Active in Patients with Advanced Myeloid Malignancies: A Single Institution Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3899-3899
Author(s):  
Kara Cicero ◽  
Mark L Heaney ◽  
Todd L. Rosenblat ◽  
Nicole Lamanna ◽  
Joseph G. Jurcic ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Research Funding ◽  
Response Rate ◽  
Cell Transplant ◽  
Secondary Aml ◽  
Myeloid Malignancies ◽  
Prior Therapy ◽  
Poor Risk ◽  
Highly Active

BACKGROUND: Despite recent advances, outcomes remain poor in secondary and relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We previously demonstrated that combination thioguanine (6TG) and decitabine restores therapeutic efficacy in vitro in R/R AML (O'Dwyer K et al. Blood 2010;114:2657). Based on these data, we completed a Phase I dose-escalation study of 6TG with decitabine in advanced myeloid malignancies with an overall response rate (ORR) of 67% and median progression-free survival (PFS) of 42 weeks in responding patients (Lee DJ, et al. Blood 2016;128:2816). Moreover, 5 of the 6 study participants who had previously received a hypomethylating agent (HMA) responded, suggesting that 6TG in combination with decitabine can overcome HMA resistance. Because of these results, a cohort of patients with high-risk and R/R AML and MDS were treated with combination 6TG and decitabine at Columbia University Irving Medical Center, and we now report our clinical experience with this regimen. METHODS: A retrospective chart review was performed of all adult patients at our institution with advanced myeloid malignancies who had received at least one cycle of 6TG and decitabine between 2013-2017. The treatment regimen utilized the maximum tolerated dose of 6TG identified in the phase I trial. Up to 2 cycles of induction with 6TG 80 mg/m2/day PO in 2 divided doses was given on Days 1-12. Decitabine 20 mg/m2 IV was given on Days 3-12. Following this, maintenance cycles consisted of 6TG on Days 1-7 and decitabine on Days 3-7 at the same doses. Treatment was continued until the time of hematopoietic stem cell transplant (HSCT), disease progression, or toxicity. The primary objective of this retrospective analysis was to determine the ORR. Secondary objectives were to evaluate PFS and overall survival (OS) in this population. RESULTS: Forty-two patients were identified, 55% of whom were female, with a median age of 68 years (range, 23-83 years). Thirty-three percent of the patients had secondary AML; 62% had R/R AML; 2% had R/R MDS; and 2% had chronic myelomonocytic leukemia. By ELN genetic risk stratification, 38% were adverse-risk, 43% were intermediate, and 17% were favorable, while 2% were unknown. However, 36 (86%) patients failed prior therapy, suggesting that nearly all of the treated patients were poor-risk. Nineteen (45%) patients had received prior HMA therapy, and 6 (14%) had undergone previous HSCT. Patients received a median of 2 cycles of therapy (range, 1-10). Five (12%) patients achieved complete remission (CR), 7 (16%) obtained a CR with incomplete count recovery (CRi/p), and 2 (5%) had morphologic leukemia-free state (MLFS), for an ORR of 33% (CR+CRi/p+MLFS). One notable patient who achieved CR was a 73-year-old with secondary AML, complex cytogenetics, and a TP53 mutation who subsequently went on to HSCT. Another 5 (36%) responders had complex karyotypes or poor-risk genetics. Ten of the 14 responders (71%) failed prior therapy. Of the 19 who had received prior HMA therapy, 6 (32%) responded. Six of 14 (43%) responders proceeded to HSCT. Two additional patients had significant blast reduction and underwent HSCT. Responses and maximum blast reduction were obtained after two cycles of therapy. For the responders, the median PFS was 38 weeks (range, 11-not reached), while the median OS was 43 weeks (range, 11-not reached). CONCLUSIONS: Combined 6TG and decitabine is a highly active regimen in advanced myeloid malignancies, with an ORR of 33% in this cohort, and median PFS and OS of 38 and 43 weeks, respectively, in responding patients. This compares favorably to the expected response rate of 10-20% with decitabine monotherapy in this poor-risk population consisting of mostly secondary and R/R AML. These data also confirm our prior phase I study findings that the addition of 6TG to decitabine can overcome prior HMA resistance, with 32% of those who had previously failed HMA therapy responding. This combination remains a viable therapeutic option for elderly and unfit patients with high-risk and R/R AML who cannot tolerate intensive chemotherapy. Disclosures Heaney: BMS: Research Funding; Partner Therapeutics: Consultancy; Roche: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; AbbVie: Consultancy; Deciphera: Research Funding; Constellation: Research Funding; Blueprint: Research Funding; CTI: Research Funding. Lamanna:Ming: Research Funding; Celgene: Consultancy; Oncternal: Research Funding; TG Therapeutics: Research Funding; Infinity/ Verastem: Research Funding. Jurcic:Syros Pharmaceuticals: Research Funding; Astellas: Research Funding; AbbVie Inc: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Incyte: Consultancy; Kura Oncology: Research Funding; Forma Therapeutics: Research Funding; Genentech: Research Funding; Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Frattini:Celgene: Employment, Equity Ownership; Lin Bioscience: Consultancy. Lee:Abbvie: Research Funding; Roche: Research Funding; Tolero: Research Funding; Forty Seven, Inc.: Research Funding; Bayer: Research Funding.

Results of a phase I study of clofarabine (CLO) plus cyclophosphamide (CY) in adult patients (pts) with relapsed and/or refractory acute lymphoblastic leukemia (ALL)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7020-7020
Author(s):  
S. Faderl ◽  
D. A. Thomas ◽  
V. Gandhi ◽  
X. Huang ◽  
G. Borthakur ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Lymphoblastic Leukemia ◽  
Nyha Class ◽  
Single Agent ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Infectious Complications ◽  
Acute Leukemias ◽  
Grade 3

7020 Background: CLO is a second generation nucleoside analog with FDA approval for children with ALL relapse. Single agent CLO in adult ALL was less active so that combinations of CLO with other active agents are pursued. As CLO inhibits DNA repair following exposure to DNA damaging agents, we designed a phase I study of the combination of CLO with CY. Methods: Pts ≥ 21 years (yrs) with primary refractory or relapsed ALL, NYHA class < 3, and a cardiac ejection fraction ≥ 45% were eligible. The continual reassessment method (CRM) was used to determine the maximum tolerated dose (MTD) from 4 pre-defined dose levels. The starting dose level was CLO 40 mg/m2 i.v. daily x 3d and CY 200 mg/m2 i.v. q12h x 3d. For cohort 2, CY was 300 mg/m2 and cohorts 3 and 4 maintained these doses with the treatment duration extended to 4 and 5 days, respectively. Results: Thirty pts have been enrolled. Median age was 28 yrs (range 21–72). Twenty-one pts had pre-B ALL, 5 pts pre-T/T ALL, 1 pt mature B ALL, and 3 pts biphenotypic acute leukemias. Karyotype was diploid in 10 pts and 2 pts had Ph+ ALL. Median number of prior regimens was 2 (1–5). Seven (23%) pts were primary refractory. Among the remainder, preceding median remission duration was 8.6 mos (1–39 mos). Five pts were treated in cohort 1 and 25 in cohort 2. One (20%) pt in cohort 1 and 9 (36%) in cohort 2 experienced DLTs (≥ grade 3) including transaminase elevations, diarrhea, hyperbilirubinemia, and (1 pt each) elevation of creatinine/renal failure, lipase elevation, rash, nausea/vomiting. Evaluable for response were 28 pts: 3 CR (one pt in cohort 1) and 1 marrow CR (OR 14%). All pts had pre-B ALL. One pt had Ph+ ALL, and one was primary refractory to HCVAD. Three early deaths due to infectious complications occurred (all in cohort 2). Conclusions: The MTD for this combination is CLO 40 mg/m2 i.v. daily x 3d and CY 200 mg/m2 i.v. q12h x 3d. DLT are mainly GI-related. A phase II extension is ongoing and will focus on efficacy data. [Table: see text]

Pralatrexate Induces Responses in Patients with Highly Refractory Peripheral T-Cell Lymphoma (PTCL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1678-1678 ◽  
Author(s):  
Kerry J. Savage ◽  
Andrei R. Shustov ◽  
Andre Goy ◽  
Steven M. Horwitz ◽  
Barbara Pro ◽  
...  
Keyword(s):  
Combination Chemotherapy ◽  
Research Funding ◽  
International Workshop ◽  
Phase 1 ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
Median Number ◽  
Folic Acid Supplementation ◽  
Refractory Disease ◽  
Prior Therapy

Abstract Abstract 1678 Poster Board I-704 Background The outcome of patients with PTCL is poor and the majority of patients ultimately have refractory disease to a variety of agents, including standard therapy with CHOP or CHOP-like regimens. Pralatrexate is a rationally designed antifolate that has a high affinity for the reduced folate carrier-1 (RFC-1) and is likely to be retained longer within cancer cells due to efficient polyglutamation by folylpolyglutamyl synthetase. Phase 1 and 2 clinical trials have shown that pralatrexate is safe and active in hematologic malignancies including relapsed or refractory PTCL (O'Connor OA, JCO 2009:10.1200/JCO.2008.20.8470). The PROPEL study, a pivotal, international, Phase 2 single-arm trial, evaluated pralatrexate in patients with relapsed or refractory PTCL who had a median of 3 prior therapies. Pralatrexate treatment was well tolerated and showed an overall response rate of 28% (30/109 patients) by central independent review. The objective of this current analysis was to characterize the treatment response among patients who were considered to have refractory disease, defined as showing 1) no evidence of response to their most recent prior therapy or 2) no evidence of response to all prior therapies. Methods Patients received pralatrexate 30 mg/m2 once weekly for 6 weeks in 7-week cycles, with vitamin B12 and folic acid supplementation. Response to pralatrexate was assessed after each odd-numbered treatment cycle and was based on rigorous centralized review of imaging and clinical data using the International Workshop Criteria (Cheson BD, JCO 1999;17:1244). Results The most commonly used prior therapies were CHOP-based chemotherapy (70%), platinum-based multi-agent chemotherapy (41%), and non-platinum containing combination chemotherapy (39%). Eighteen (16%) patients received autologous stem-cell transplantation (SCT) prior to the PROPEL study. Of the 109 patients who were evaluable for response, 69 (63%) patients had no evidence of response to the most recent therapy and 26 (25%) patients had had no evidence of response to any therapy. The ORR for the 69 patients with no evidence of response to their most recent prior therapy was 25% (n=17) according to central review and 36% (n=25) according to investigator review. The median duration of response was 99 days (range, 41-535) by central review. The median number of prior systemic therapies for these 69 patients was 3 (range, 1-11). Twenty-six patients had no evidence of response to any prior therapy before initiating pralatrexate, having received a median of 2.5 prior therapies (range, 1-7). Five (19%) of these patients responded to pralatrexate by central review and 7 (27%) responded by investigator review. The duration of centrally reviewed response to pralatrexate in the patients with no evidence of response to any prior therapy was 54, 57, 69, 78, and 306 days. Conclusions Pralatrexate has demonstrated activity in patients with PTCL who were refractory to their most recent therapy, including patients who were refractory to all prior therapies. Responses to pralatrexate were observed in patients with disease that was refractory to a range of therapies used in PTCL, including SCT and a variety of single agent and combination chemotherapy regimens, suggesting that pralatrexate can overcome mechanisms of drug resistance in this population. Disclosures Savage: Allos Therapeutics, Inc.: Consultancy, Honoraria. Horwitz:Allos Therapeutics, Inc: Consultancy, Research Funding. Pro:Allos Therapeutics, Inc.: Research Funding. Fruchtman:Allos Therapeutics, Inc.: Employment.

An Open-Label Phase I Study of the Safety and Efficacy of RAD001 in Combination with Lenalidomide in the Treatment of Patients with Relapsed and Relapsed/Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3856-3856 ◽  
Author(s):  
Noopur Raje ◽  
Paul Richardson ◽  
Parameswaran N Hari ◽  
Anuj Mahindra ◽  
Sarah Kaster ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Oral Steroid ◽  
High Dose ◽  
Advisory Committees ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 3856 Poster Board III-792 Background Lenalidomide (Revlimid®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (MM) patients following ≥1 prior therapy. mTOR inhibitor RAD001 has been studied as a single agent in MM, and although well tolerated, did not have single agent activity. Given the increased toxicity noted with pulsed high dose steroids, we sought to study a non-steroid containing oral regimen for the treatment of relapsed MM predicated upon our previous studies which demonstrated synergistic anti-MM activity of mTOR inhibitors when combined with len. Here, we extended our in vitro observations to a phase I clinical trial combining RAD001 with len in patients with relapsed or refractory MM. The primary objective was to assess toxicity of this combination and to determine the maximum tolerated dose (MTD). The secondary objective was to determine the activity of this combination. Methods Patients with relapsed and refractory MM were assigned to len and RAD001 to be taken for 21 days of a 28 day cycle. Dose escalation followed a modified Fibonacci design. Patients were allowed to continue therapy until disease progression or unacceptable toxicity. Patients received concomitant anti-thrombotic (aspirin 81 or 325 mg/day) therapy. Response was assessed according to modified EBMT and Uniform Criteria, and toxicities were assessed using NCI CTCAE v3.0. Results Eighteen MM patients have been enrolled to date. One patient in cohort 1 (Len: 10mg and RAD001: 5 mg x 21 days) developed grade 3 neutropenia requiring expansion of the cohort. Cohort 2 (Len: 15mg and RAD001: 5 mg x 21 days) also required expansion because of grade 4 thrombocytopenia noted in 1 patient. Dose limiting toxicities included grade 4 neutropenia and thrombocytopenia in 2/3 patients in cohort 3 (Len: 20mg and RAD001: 5 mg x 21 days). The MTD for patients with MM was therefore declared at 15 mg of len and 5mg of RAD001 for 21 days with a 7 day rest period. Apart from the hematological toxicities expected with the combination, patients otherwise tolerated the regimen well. Most common (≥10%) grade 1 / 2 events included nausea, fatigue, dyspnea, diarrhea, constipation, neuropathy and muscle cramps, all of which were manageable with supportive care. No thromboembolic events were noted. Grade 3 / 4 adverse events ≥ 5% included thrombocytopenia (11%) and neutropenia (22%). Fifteen patients have finished at least 2 cycles of therapy: 8 of 15 patients have either stable disease (SD: 1), minimal response (MR: 5) or a partial response (PR: 2), including 7 of 9 patients treated at the recommended MTD for an overall response rate (MR or better) of 50% (90% CI: [30.76%]). One patient with SD continued therapy for a total of 10 cycles, without significant toxicities. Conclusions The combination of Len plus RAD001 is a well tolerated regimen with predictable hematological toxicities. Promising responses were noted in this heavily pretreated patient population. This combination provides an oral steroid free combination alternative strategy which warrants future evaluation in phase II studies. Disclosures: Raje: Astrazeneca : Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: RAD001 not labelled for use in myeloma. Richardson:Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hari:Celgene: Research Funding, Speakers Bureau. Laubach:Novartis:. Ghobrial:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Adams:Novartis: Employment. Makrides:Celgene: Employment.

Phase I/II Study with Single Agent Everolimus (RAD001) in Patients with Relapsed or Refractory Multiple myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3850-3850 ◽  
Author(s):  
Andreas Guenther ◽  
Philipp Baumann ◽  
Renate Burger ◽  
Wolfram Klapper ◽  
Ralf Schmidmaier ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Research Funding ◽  
Cell Cancer ◽  
Single Agent ◽  
Study Drug ◽  
Fixed Dose ◽  
Bone Marrow Biopsies ◽  
Refractory Multiple Myeloma ◽  
Dose Levels

Abstract Abstract 3850 Poster Board III-786 Introduction The mammalian target of rapamycin (mToR) plays an important role in multiple myeloma (MM), since it is involved in the PI3K-AKT pathway which can be activated by stimulation with growth and survival factors such as interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1) or the loss of the tumor suppressor PTEN. Inhibition of mToR blocked myeloma cell growth in vitro as well as in preclinical animal models. The mToR inhibitor everolimus (RAD001) is approved for immunosuppression and for the treatment of renal cell cancer. In an investigator-initiated phase I/II open label trial, patients ≥ 18 years with relapsed or refractory multiple myeloma (MM) were included after at least two lines of previous treatment. The patients received a fixed dose of oral everolimus for six months. The cohorts had 3 to 6 participants. The phase I part of the trial followed a classical dose-escalation design with three planned dose levels (5 mg, 7.5 mg and 10 mg). Patient benefiting from study drug were allowed to continue with treatment. To obtain insights into the biological activity of everolimus, serum dose levels were monitored and bone marrow biopsies and aspirates were performed three times (at screening, after four weeks and after six months of treatment). Results The primary endpoint of the phase I part was safety. Currently, 12 patients were screened and 11 enrolled in the trial (10 male and 1 female, age from 52 to 71 years). One patient withdrew his consent in the first four weeks of treatment and had to be replaced for safety and efficacy assessment. Since no DLT were observed, the intended final daily dose of 10 mg everolimus could be reached. Only one of four SAE during treatment was assessed to be possibly related to the study drug. Except for one grade 4 thrombocytopenia, no > grade 3 AE were observed during treatment. Remarkably, few infectious complications (≤grade 2) were seen despite the known immunosuppressive activity of everolimus. Anti-myeloma activity was documented in 5 out of 7 evaluable patients. One partial response in a heavily pre-treated patient and stable disease in four additional patients were seen. The observed rate of responses and clinical benefit fulfills the criteria defined in the protocol to enter the phase II part of the trial after completing phase I. The individual serum dose levels varied widely and response seemed to correlate to the achieved everolimus dose level. Conclusion Everolimus given orally at doses of 5 mg to 10 mg daily showed an acceptable safety profile in heavily pre-treated multiple myeloma patients and the observed responses even at suboptimal dose levels are promising. Further evaluation of everolimus, alone and in combination with other drugs, is warranted. Disclosures: Guenther: Novartis: Consultancy, Research Funding. Off Label Use: Everolimus is not approved for multiple myeloma. Baumann:Novartis: Consultancy, Research Funding. Schmidmaier:Novartis: Consultancy, Research Funding. Gramatzki:Novartis: Consultancy, Research Funding, Speakers Bureau.

Carfilzomib: High Single Agent Response Rate with Minimal Neuropathy Even In High-Risk Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1938-1938 ◽  
Author(s):  
Ravi Vij ◽  
Jonathan L. Kaufman ◽  
Andrzej J Jakubowiak ◽  
A. Keith Stewart ◽  
Sundar Jagannath ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Impaired Renal Function ◽  
Response Rate ◽  
Single Agent ◽  
Advisory Committees ◽  
High Risk Disease ◽  
All Treatment

Abstract Abstract 1938 Background: Carfilzomib (CFZ), a selective, epoxyketone proteasome inhibitor, produces potent, sustained proteasome inhibition and lacks many of the off-target activities associated with bortezomib (BTZ). Durable single-agent activity with CFZ has been observed in patients (pts) with relapsed/refractory multiple myeloma (R/R MM) who have received multiple prior therapies as well as in pts with advanced stage disease or significant comorbidities (Jagannath et al. ASCO 2009 Meeting. Abstract 8504). PX-171-004, is an ongoing Phase 2 study of single-agent CFZ in pts with relapsed or refractory MM following 1–3 prior therapies. Here we present updated data on the BTZ-naïve pts and report on activity observed in pts with significant comorbidities or poor-risk cytogenetic or FISH markers for myeloma. Methods: Enrolled pts received either 20 mg/m2 for all treatment cycles, or a stepped-up, dose-escalating regimen of 20 mg/m2 for Cycle 1 and 27 mg/m2 for all treatment cycles thereafter. CFZ was administered on Days 1, 2, 8, 9, 15 and 16 every 28 days (one cycle), for a maximum of 12 cycles. Dexamethasone, 4mg, was administered prior to CFZ in Cycle 1 only. For the present analyses, pts were stratified according to several baseline criteria including ECOG performance score, cytogenetic or FISH markers of high-risk disease per mSMART criteria [del17p, t(4;14), t(14;16), del13 by karyotype and hypodiploidy] and serum ß2-microglobulin. The primary endpoint was overall response rate (ORR) per International Uniform Response Criteria for Multiple Myeloma. Results: Data are available for 110 BTZ-naïve pts. Baseline pt characteristics included: 60% of ECOG PS ≥1; 53% baseline neuropathy Grade 1/2; 30% moderately impaired renal function (CrCl <60 mL/min), and 17% diabetes. Approximately 13% of pts had cytogenetic or FISH markers of poor prognosis. The ORR for the entire BTZ-naïve population was 48%; the ORR for BTZ-naïve pts receiving 20–27 mg/m2 was 54%. The ORRs stratified according to dose and baseline measurements are detailed in the following table. The most common treatment-emergent AEs, regardless of relationship to study drug, were fatigue (61%), nausea (43%), anemia (39%), dyspnea (36%), cough (34%), headache (31%), thrombocytopenia and upper respiratory infections (30% each) and were primarily ≤ Grade 2 in severity. Grade 3/4 AEs occurring in >5% of pts included lymphopenia, neutropenia, pneumonia, thrombocytopenia, anemia and fatigue. Of note, there were no discontinuations for peripheral neuropathy and only 1 pt with impaired renal function at baseline was discontinued for creatinine increases. Twenty-four pts remain on study and 23% have completed the protocol-specified 12 cycles of therapy. Seventeen pts (20%) elected to continue CFZ on an extended treatment protocol (PX-171-010); no cumulative toxicities have been noted. Conclusions: Single-agent CFZ achieves high response rates in BTZ-naïve pts with relapsed myeloma, with minimal neuropathy, even in the setting of high-risk disease. In addition, single-agent CFZ continues to demonstrate long-term tolerability even in pts with comorbid conditions, including renal insufficiency and diabetes, who may benefit from a steroid-sparing treatment regimen. The data from this ongoing trial show that CFZ is a promising new treatment for multiple myeloma in the relapsed or refractory setting. Disclosures: Vij: Onyx: Honoraria. Kaufman:Celgene: Consultancy, Research Funding; Millenium: Consultancy; Merck: Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotec: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jagannath:Millenium, OrthoBiotec, Celgene, Merck, Onyx: Honoraria; Imedex, Medicom World Wide, Optum Health Education, PER Group: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Alsina:Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. Gabrail:Millenium: Research Funding. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Speakers Bureau. Le:Onyx Pharmaceuticals: Employment. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding.

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