Maximum Planned Dose Research Articles

Results of Cynk-001-AML-001: A Phase I Multi-Dose Study Evaluating the Safety, Tolerability, and Persistence of Cynk-001 in Adults with De Novo or Secondary Acute Myeloid Leukemia in Morphologic Complete Remission with Minimal Residual Disease or Relapsed/Refractory AML

Introduction: Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease often with suboptimal outcomes. While progress has been achieved in the treatment of AML, relapse remains a significant challenge. Novel therapeutic options aimed at attaining minimal residual disease (MRD) negative complete remission (CR) are expected to reduce the incidence of relapse and prolong survival. Evidence shows that natural killer (NK) cells can exhibit potent anti-leukemia activity against AML. CYNK-001 is a CD56+CD3- enriched, off-the-shelf, unmodified allogeneic NK cells expanded from placental CD34+ cells. Aim CYNK-001-AML-001 is a phase I multi-dose study evaluating the safety, tolerability, and persistence of CYNK-001 with or without recombinant human interleukin-2 (rhIL-2) in adults with de novo or secondary acute myeloid leukemia (AML) in morphologic complete remission (CR) with minimal residual disease (MRD) or relapsed/refractory (R/R) AML. Methods This Phase I, single-arm, dose escalation clinical trial (NCT04310592) enrolled patients 18-80 years with R/R AML or patient in MRD positive CR. Two lymphodepletion regimens were assessed. Patients in cohorts 1-3 underwent standard lymphodepletion with fludarabine (25 mg/m2/day) and cyclophosphamide (300 mg/m2/day) on days -5, -4 and -3. Subsequent cohorts received enhanced lymphodepletion with fludarabine (30 mg/m2/day) and cyclophosphamide (900 mg/m2/day) on days -6, -5, -4 and -3. Escalating doses of NK cells were administered following a standard 3+3 design, with 2 separate arms (MRD+ arm and R/R arm) starting with cohort 4. A starting dose of 600 million cells on days 0, 7, and 14 was escalated to a maximum dose of 1.8 billion cells on days 0, 7, 14 and 21. The primary objective of the study was to determine the maximum tolerated dose (MTD) or maximum planned dose (MPD) of CYNK-001 and to assess the safety of multiple infusions of CYNK-001 administered using a flat, non-weight-based dose as assessed by the frequency and severity of adverse events (AE). The secondary objective was to assess the clinical efficacy of CYNK-001 in AML subjects. Results 28 patients (17 with R/R AML and 11 with MRD-positive AML) were enrolled during dose escalation, and 27 received CYNK-001. The highest dose of NK cells administered was 1.8 billion cells X 4 in cohort 6b (patients with R/R AML). Treatment was well tolerated with no dose limiting toxicities (DLTs) even at the highest dose. No cases of neurotoxicity or GvHD were reported. Four cases of grade 2 CRS were reported but there were no cases of ≥ grade 3 CRS. Two incidences of grade 4 thrombocytopenia and one grade 4 decreased white blood cell count were noted in patients who had received enhanced lymphodepletion. In R/R AML patients treated with the highest dose of CYNK-001, 2 of 4 patients achieved an objective response of Morphologic Leukemia-Free State (MLFS) on Day 28. One of these patients has maintained a response to D120 and is continuing follow up. One of 3 patients with MRD +ve AML treated with 3 doses of 1.8 billion CYNK-001 cells per dose achieved MRD negativity until day 120 at which time a blast count of 1.6% was observed. Conclusion Treatment with CYNK-001 showed biological activity as evidenced by achievement of MLFS in R/R AML patients and eradication of AML MRD positivity in AML patients in morphologic CR. Therapy was generally well-tolerated, with no dose-limiting toxicities observed with even the highest dose of CYNK-001. This trial yielded important insights into the optimal approach to lymphodepletion and the potential clinical efficacy of allogeneic NK cells in R/R AML. Based on these results, this trial is now closed to further enrollment and future development activities will focus on next generation NK cell therapies edited to optimize persistence and efficacy and limit the requirement for enhanced lymphodepletion.

EFFICACY OF AN TRANSARTERIAL CHEMOEMBOLIZATION (TACE) WITH MICROSPHERES FROM POLY(VINYL ALCOHOL) LOADED OF DOXORUBICIN AGAINST ANAPLASTIC CARCINOMA VX2 IN RABBITS

The research is devoted to the study of the efficacy of new Russian microspheres loaded by (MC/DOX) of 0.4-0.6 mm diameter on a basis of cryogel with poly(vinyl alcohol) intended for a transarterial chemoembolization (TACE). MC/DOX in dose of of 0.5-1.0 ml contained Doxorubicin of 16 mg or 32 mg were transarterially injected in a single dose to rabbits (n = 24) with the VX2 anaplastic carcinoma of the moderate volume of 3-5 cm2 which developed in femur muscles (the pool of a femoral artery). The time of complete released of DOX was 16 days up to dose (a cumulative dose) 16 and 32 mg, respectively. The efficacy was controlled with the decrease of the tumor growth rate and significant inhibition through embolization of turnpike blood of a tumor zone under radiological monitoring. MC/DOX were shown both to give rise in the regression of tumor nodes and reduce the growth rate by 2.0-2.5 times in dependence on the dose value. The reliable therapeutic prize of MC/DOX against embolization effect of 0.5 ml MC that achieved at the maximal DOX cumulative dose of 32 mg consists in the achievement of regression of VX2 up to 50% at 5 of 6 rabbits with the development of the cure pathomorphological effect of III degree which is characterized by the gain in the area of a necrosis by 1.5-3.0 times. The maximal efficient cumulative dose of 32 mg Doxorubicin exceeds value of Maximum Planned Dose (MPD) of Doxorubicin by 6 times for systemic injection to rabbits. The embolizing effect of MC/DOX in the form of blocking of shallow arterioles at preservation of turnpike blood supply did not depend on the size of the applied dose. The reliable antineoplastic effect revealed on this model allows good out perspective for a transarterial chemoembolization of a tumor with MC/DOX.

A Multicenter, Open-Label, Phase 1b Study of Carfilzomib, Cyclophosphamide, and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients (CHAMPION-2)

▪Introduction: Carfilzomib is an irreversible second-generation proteasome inhibitor that is currently approved for the treatment of relapsed or refractory multiple myeloma (MM). The primary objective of the CHAMPION-2 study was to determine the maximum tolerated dose (MTD) of carfilzomib when used with cyclophosphamide and dexamethasone (KCyd) for newly diagnosed MM, and secondary objectives were to evaluate the overall response rate (ORR), time to response (TTR), and safety of KCyd. Methods: This was a multicenter, open-label, single-arm, phase 1b study that enrolled patients 18 years or older with newly diagnosed symptomatic MM. Patients deferring transplant and transplant-ineligible patients were allowed. Treatment was given in 28-day cycles and continued for 8 cycles, or until unacceptable toxicity, withdrawal of consent, or progressive disease. A traditional 3+3 dose escalation scheme was used to determine the MTD of carfilzomib, with the following dose levels evaluated: 36, 45, and 56 mg/m2. Carfilzomib (30-minute infusion) was administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle, beginning with 20 mg/m2 on days 1 and 2 of cycle 1, then stepping up to the assigned dose level. In each cycle, cyclophosphamide (oral, 300 mg/m2) was administered on days 1, 8, and 15, and dexamethasone (oral or intravenous, 40 mg) was administered on days 1, 8, 15, and 22. An expansion cohort was enrolled at the established MTD or the maximum planned dose (MPD). Results: There were no dose-limiting toxicities observed at any of the dose levels evaluated, and thus the MPD of 56 mg/m2 was brought forward into dose expansion. A combined total of 16 patients (dose escalation + dose expansion) received carfilzomib at 56 mg/m2. The median age of patients who received KCyd at 56 mg/m2 was 65 years (range, 49-81), 56.3% were male, and 93.8% had an ECOG performance status of 0 or 1. At 56 mg/m2,the ORR was 87.5% (95% CI, 61.7%-98.4%), and best overall responses were complete response (n = 1); very good partial response (n = 7); partial response (n = 6); and stable disease (n = 2). The median TTR for patients who received the 56 mg/m2 dose and achieved partial response or better was 1 month. At 56 mg/m2,the most common adverse events of any grade were nausea (68.8%), cough (62.5%), diarrhea (56.3%), anemia (50.0%), fatigue (50.0%), and headache (43.8%), and the most common grade ≥ 3 adverse events were anemia (25.0%), hypokalemia (18.8%), neutropenia (18.8%), acute kidney injury (12.5%), and decreased white blood cell count (12.5%). Any-grade peripheral neuropathy was reported for 1 patient treated with the 56 mg/m2 dose. The mean number of treatment cycles started among patients who received the 56 mg/m2 dose was 7 (range, 3-8). In total, 6 of the 16 patients who received carfilzomib at 56 mg/m2 did not complete the 8 cycles of study treatment: 1 patient discontinued due to progressive disease (which manifested during a break in treatment for renal insufficiency), 1 patient withdrew from the study, and 4 patients discontinued treatment because of adverse events. Adverse events that led to treatment discontinuation were acute renal failure (n = 1), creatinine increase and dehydration (n = 1), intermittent nausea (n = 1), and urinary tract infection (n = 1). One patient in the 45 mg/m2 cohort experienced death due to sudden cardiac arrest; no deaths in the 36 or 56 mg/m2 cohorts occurred during the study. Conclusions: Carfilzomib administered at 56 mg/m2 twice weekly in combination with cyclophosphamide and dexamethasone was effective and showed acceptable toxicity for treating patients with newly diagnosed MM. The CHAMPION-2 study suggests that KCyd may be considered for first-line treatment of MM, including for patients not eligible for transplant.Acknowledgments: This study was supported by Onyx Pharmaceuticals, Inc. an Amgen, Inc. subsidiary. The authors would like to thank Jesse Potash of Amgen, Inc. for medical writing assistance. DisclosuresBoccia:Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; Gilead: Speakers Bureau; Eisai: Consultancy, Honoraria, Speakers Bureau. Conkling:USOncology Research: Research Funding; Amgen Inc.: Research Funding. Harb:Amgen Inc.: Consultancy. Yang:Amgen Inc.: Employment, Equity Ownership. Pinchasik:Amgen Inc.: Employment, Equity Ownership. Kimball:Amgen Inc.: Employment, Equity Ownership. Berenson:OncoTracker: Employment, Equity Ownership.

A Phase 1, Multicenter Study of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone in Patients with Proteasome Inhibitor Exposed and Lenalidomide-Refractory Myeloma (Trial MM-005)

A Phase 1, Multicenter Study of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone in Patients with Proteasome Inhibitor Exposed and Lenalidomide-Refractory Myeloma (Trial MM-005)

A Single-Arm, Open-Label, Multi-Center Phase I/II Study Of The Combination Of Panobinostat and Carfilzomib In Patients (pts) With Relapsed Or Relapse/Refractory Multiple Myeloma (MM)

BackgroundProteasome inhibitors (PI) such as bortezomib and carfilzomib (CFZ) have improved the treatment of MM; however, resistance invariably develops and MM remains an incurable disease. Changes in histone modification are commonly found in human cancers including MM, and several histone deacetylase inhibitors (HDACi) are in clinical development. Preclinical studies demonstrate synergistic anti-MM activity of the combination of HDACi with PI through dual inhibition of the proteasome and aggresome pathways. Panobinostat (PAN) is an oral pan-HDACi which has shown synergy with PIs in clinical studies. In this study, we evaluate the safety and efficacy of the PAN/CFZ combination in pts with relapsed and relapsed/refractory MM. Here we present the updated results of this ongoing trial. MethodsPatients with MM who had relapsed after at least one prior treatment were eligible to participate. In the dose escalation portion of the study a standard 3+3 design was used to determine the maximum tolerated dose (MTD) of 4 planned dose levels with the combination of CFZ and PAN. PAN was administered orally three times weekly during weeks 1 and 3 of each cycle (Days 1, 3, 5, 15, 17, 19). CFZ was administered IV over 30 min on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The 4 dose levels tested were DL 1, defined as 20 mg PAN and 20/27 mg/m2 CFZ; DL 2, defined as 20 mg PAN and 20/36 mg/m2 CFZ; DL 3, defined as 20 mg PAN and 20/45 mg/m2 CFZ; and DL 4, defined as 30 mg PAN and 20/45 mg/m2 CFZ. Treatment was continued until PD or intolerable toxicity. The primary efficacy endpoint was the overall response rate (ORR) (≥ PR). Secondary end points were time to progression (TTP), progression-free survival (PFS) and overall survival (OS), calculated using Kaplan-Meier methods. Adverse Events (AEs) were assessed according to CTCAE Version 4 and responses were assessed using IMWG criteria (plus MRs as per the EBMT criteria). The MPD (maximum planned dose) was further explored in the expansion phase. Results10 patients were treated in the dose escalation portion of the study. No DLTs were observed. DL 4 was further explored and 31 patients were enrolled in the expansion phase of the study. As of the data cutoff of 5/31/2013, 44 pts were accrued to the trial, including 34 pts on the eventual expanded DL 4. The median age of pts was 66 (41-83); most patients were ISS stages 2 and 3; 38% of pts had adverse prognostic cytogenetics or FISH, including 23% with del 17p. The median number of prior therapies was 3 (1-6) including 89% with prior bortezomib, 89% with prior immune modulating drugs (IMiDs), 34% with prior stem cell transplants. Thirty six percent of pts were refractory to bortezomib, 30% were refractory to IMiDs, 14% were refractory to both bortezomib and IMiDs, and 43% were refractory to their last treatment regimen. Twenty seven (61%) pts remain on active treatment. Forty five percent of pts experienced ≥ grade 3 hematologic-related AEs, the most common being G3 thrombocytopenia (30%) and neutropenia (20% G3 and 2% G4). Thirty four percent of pts experienced ≥ grade 3 non-hematologic AEs, the most common being fatigue (11% G3) and nausea/vomiting (9% G3). The most salient of all grade AEs were nausea/vomiting (39% G1, 20% G2, 9% G3, 0 G4) and thrombocytopenia (14% G1, 27% G2, 30% G3, 0 G4). Peripheral neuropathy was rare (5% G1, 2% G2, 0 G3/4). In pts treated on DL 4 (30 mg PAN and 20/45 mg/m2 CFZ), late cycle dose reductions for PAN were common (59% of pts) and the median PAN dose delivered was 23.4 mg. CFZ dose reductions were rare (18% of pts) and the median CFZ dose was 40.8 mg/m2. The ORR was 64% with 31% ≥VGPR and 30% PR. In addition, there were 5% MR, 26% SD and 5% PD. The ORR for bortezomib exposed pts, bortezomib refractory pts and dual bortezomib and IMiD refractory pts was 60%, 67% and 66%, respectively. With a median follow up of 6.3 months, the PFS at 6 and 12 months was 63% and 41% respectively. The OS was 83% at both 6 and 12 months and the median TTP was 8.6 months. ConclusionsThe combination of PAN and CFZ is feasible and effective in this relapsed/refractory MM population. Due to dose reductions required for PAN and no MTD reached, 2 further dose levels will be explored with plans to do a parallel dose expansion if tolerated. Disclosures:Off Label Use: Off-label use of the combo Panobinostat and Carfilomib in the treatment of relapsed/refractory Multiple Myeloma.

Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma

AbstractWe previously reported a phase 1b dose-escalation study of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in relapsed or progressive multiple myeloma where the maximum planned dose (MPD) was carfilzomib 20 mg/m2 days 1 and 2 of cycle 1 and 27 mg/m2 days 8, 9, 15, 16, and thereafter; lenalidomide 25 mg days 1 to 21; and dexamethasone 40 mg once weekly on 28-day cycles. Herein, we present results from the phase 2 dose expansion at the MPD, focusing on the 52 patients enrolled in the MPD cohort. Median follow-up was 24.4 months. In the MPD cohort, overall response rate (ORR) was 76.9% with median time to response of 0.95 month (range, 0.5-4.6) and duration of response (DOR) of 22.1 months. Median progression-free survival was 15.4 months. ORR was 69.2% in bortezomib-refractory patients and 69.6% in lenalidomide-refractory patients with median DOR of 22.1 and 10.8 months, respectively. A median of 9.5 (range, 1-45) carfilzomib cycles were started with 7.7% of patients requiring carfilzomib dose reductions and 19.2% discontinuing CRd due to adverse events (AEs). Grade 3/4 AEs included lymphopenia (48.1%), neutropenia (32.7%), thrombocytopenia (19.2%), and anemia (19.2%). CRd at the MPD was well tolerated with robust, rapid, and durable responses. This trial was registered at clinicaltrials.gov as #NCT00603447.

A phase I/II study of carfilzomib 2–10-min infusion in patients with advanced solid tumors

Purpose Tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of carfilzomib, a selective proteasome inhibitor, administered twice weekly by 2–10-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 in 28-day cycles, were assessed in patients with advanced solid tumors in this phase I/II study. MethodsAdult patients with solid tumors progressing after ≥1 prior therapies were enrolled. The dose was 20 mg/m2 in week 1 of cycle 1 and 20, 27, or 36 mg/m2 thereafter. The maximum tolerated dose or protocol-defined maximum planned dose (MPD) identified during dose escalation was administered to an expansion cohort and to patients with small cell lung, non-small cell lung, ovarian, and renal cancer in phase II tumor-specific cohorts.ResultsFourteen patients received carfilzomib during dose escalation. The single dose-limiting toxicity at 20/36 mg/m2 was grade 3 fatigue, establishing the MPD as the expansion and phase II dose. Sixty-five additional patients received carfilzomib at the MPD. Adverse events included fatigue, nausea, anorexia, and dyspnea. Carfilzomib PK was dose proportional with a half-life <1 h. All doses resulted in at least 80 % proteasome inhibition in blood. Partial responses occurred in two patients in phase I, with 21.5 % stable disease after four cycles in evaluable patients in the expansion and phase II cohorts.ConclusionCarfilzomib 20/36 mg/m2 was well tolerated when administered twice weekly by 2–10-min IV infusion. At this dose and infusion rate, carfilzomib inhibited the proteasome in blood but demonstrated limited antitumor activity in patients with advanced solid tumors.

A phase I study of sorafenib with FOLFIRI as first-line therapy for metastatic colorectal cancer (mCRC): Safety and efficacy results.

3633 Background: Phase I dose escalation to a maximum planned dose (MPD) o determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended-phase-II-dose (RP2D) and preliminary efficacy of sorafenib and FOLFIRI (irinotecan reduced-dose) in metastatic colorectal cancer (mCRC) patients. Methods: Starting doses: irinotecan 80 mg/m2 iv d1, sorafenib 400 mg po twice daily (bid, continuous), starting day 2. Escalations based on toxicity observed at the previous dose level (DL) up to: irinotecan 100 mg/m2 and sorafenib 800 mg bid. DLT was evaluated within the 1st study cycle (1 cycle = 2 FOLFIRI treatments). Results: 5 cohorts were concluded. All 16 ECOG PS 0-1 patients (9/7 men/women; 2/14 rectal/colon) with median age of 64, discontinued study: 10 (62%) disease progression, 4 (25%) toxicity, 1 curative surgery, 1 comorbidities. The dose levels of irinotecan (mg/m2, day1) and sorafenib (mg/day, bid, day 2-28) studied were DL1-80/400, DL2-80/600, DL3-90/600, DL4-100/600 and DL5-100/800, repeated every 4 weeks, 3 patients/DL. No DLT was observed. The MTD was not reached at the MPD (DL5). The most common ≥Gr2 treatment related adverse events (AEs) were: neutropenia 81%, HFS 69%, leucopenia 50%, fatigue 38%, anemia 31%, constipation 31%, nausea/vomiting 31%, mucositis 31%, diarrhea 25%, hypophosphatemia 25%. The most severe treatment related AEs were: Gr4: neutropenia 2 (12.5%); pulmonary embolism 1 (6%); Gr3: HFS 9 (56%), neutropenia 3 (19%), leucopenia 3 (19%), hypophosphatemia 3 (19%). Objective response rate was 56% (9 of 16 patients, 95%CI; 33-77%). Response duration was 13 months (95%CI; 5-17). Median progression-free survival and overall survival were 11 months (95%CI; 6-17) and 25 months (95%CI; 15-34), respectively. Conclusions: Combination therapy with S and modified FOLFIRI in these patients is well tolerated and demonstrates clinical efficacy at the MPD. The MTD was not reached at the MPD. Future research of this combination is warranted. Supported by Bayer Healthcare Pharmaceuticals. Clinical trial information: NCT00780169.

Final results from the phase Ib/II study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in patients with relapsed or progressive multiple myeloma.

8529 Background: Carfilzomib (CFZ) is approved in the US as single-agent treatment for patients with multiple myeloma (MM) who have progressed after bortezomib (BTZ) and an IMiD and are refractory to last line of treatment. We previously reported interim data from PX-171-006 (NCT00603447), a Ph 1b/2 study of CRd in relapsed or progressive MM (Wang et al. ASCO 2011). Herein we report final results. Methods: Patients (1–3 prior treatments) received CRd in 28-day (D) cycles—CFZ IV on D1, 2, 8, 9, 15, 16, lenalidomide (LEN) PO D1–21, and dexamethasone (dex) wkly. In phase 1, CFZ (15–27 mg/m2) and LEN (10–25 mg) doses were escalated to determine the maximum tolerated dose (MTD) with a maximum planned dose (MPD) of CFZ 20 mg/m2 D1, 2 of Cycle 1 and 27 mg/m2 thereafter, LEN 25 mg/d, and dex 40 mg/wk, followed by phase 2 expansion at MTD/MPD. Endpoints included IMWG overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and safety. Results: A total of 84 patients were enrolled since June 2008. Overall, prior treatment included BTZ (77%/18% refractory) and LEN (70%/35% refractory); 20% had high-risk cytogenetics/FISH. MTD was not reached in Ph 1, supporting expansion at the MPD (n=52, 23% BTZ refractory and 42% LEN refractory). As of Nov 2012 (median follow-up 24.4 mo): ORR was 69% overall and 76.9% at MPD with very good partial response in 36.9% and 38.5% and stringent complete response in 3.6% and 3.8%, respectively; median DOR was 18.8 (95% CI 9.7–41.5) and 22.1 mo (95% CI 9.5–NE) respectively; median PFS was 11.8 (95% CI 7.6–20.7) and 15.4 mo (95% CI 7.9–NE), respectively. Seven responders at MPD pursued other therapy and were censored for PFS.A median of 8.5 (range 1−46) CFZ cycles were started; 4% required CFZ dose reductions; 15% discontinued CFZ due to adverse events (AEs). Grade 3/4 AEs were generally consistent with earlier studies in advanced MM that used similar doses of single-agent CFZ; grade 3/4 peripheral neuropathy was 1%. Conclusions: CRd was well tolerated, providing robust and durable responses in this pt population where 35% were LEN refractory. This combination is being further evaluated in several ongoing phase 2/3 trials. Clinical trial information: NCT00603447.

Updated Results of Phase II Study of Cyclophosphamide(Cy), Bortezomib(Bz), Pegylated Doxorubicin(DOX), and Dexamethasone(dex), (CVDD), in Patients with Newly Diagnosed Myeloma:an Effective Induction Regimen for High Risk Disease

AbstractAbstract 4071 Background:The VDD treatment regimen has been shown to be effective as initial therapy for multiple myeloma, as demonstrated by a Phase II trial with overall response rates of 89% and VGPR + CR rates of 53%. Given the established synergy between bortezomib and alkylating agents, incorporating an alkylator to VDD may increase the depth of response and may improve long term outcome. We previously reported the results of a Phase I study of VDD with escalating doses of cyclophosphamide and reached the maximum planned dose (MPD) of the regimen without dose limiting toxicities. We now report updated results from the Phase II trial of CVDD in patients with newly diagnosed myeloma. Methods:Patients were treated at the MPD defined by the phase I study, and received Cy 750 mg/m2 IV on day 1, Bz 1.3 mg/m2 IV on days 1, 4, 8, 11, DOX 30mg/m2 on day 4, a Dex 20 mg on days 1, 2, 4, 5, 8, 9, 11, 12 for up to eight 21-day cycles. Patients with Gr ≥ 2 peripheral neuropathy (PNY) were excluded. Responses were assessed by International Working Group criteria. Patients were stratified in 2 cohorts by risk. Patients with high risk cytogenetics defined as the presence of one of the following at diagnosis; deletion of chromosome 13 by cytogenetics, hypodiploidy, or t(4;14, t(14;16) or deletion of 17 p by FISH, were included in the high risk cohort (HR) and all others in the standard risk cohort (SR). Patients with at least partial response (≥PR) and standard risk cytogenetics could proceed to autologous stem cell transplant (ASCT) after ≥6 cycles. Responsive patients with high risk cytogenetics completed 8 cycles of therapy. Results:Forty nine pts were treated in study and forty eight patients are evaluable for response. Median age was 57 yrs, 59% male. Twenty five % of forty nine patients had high risk myeloma. The median number of cycles completed by patients is 6 in the SR cohort and 8 in the HR cohort. The overall response rate (ORR; ≥PR) is 89% for the SR cohort and 100 % for the HR cohort. The rate of ≥VGPR was 69% and similar in both cohorts. However the rate of CR/sCR was higher in the HR cohort compared to the SR cohort at 50% and 25%, respectively. 62% patients proceeded to transplant and all had successful stem cell mobilization with G-CSF alone. At a median follow up of 24 months the median PFS or OS has not been reached, and the 2 year OS is 89.19 % for the standard risk group and 100% for the high risk group. Most common ≥ grade 3 toxicities events related to protocol treatment were myelosupression (48%), dizziness (7.7%), fatigue (6.5%), and PNY (6.5%). Conclusions:CVDD produces high quality responses and is well tolerated in newly diagnosed MM patients, regardless of their cytogenetic status. Stem cell mobilization has been successful in all patients, with transplant course in patients otherwise unremarkable. The high rate of CR rates and OS in high risk patients warrants further evaluation of this regimen in that patient population. Disclosures:Alsina:Millenium: Consultancy, Research Funding; Ortho Biotech: Research Funding. Baz:Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding.

Delivery quality assurance with ArcCHECK

Radiation therapy requires delivery quality assurance (DQA) to ensure that treatment is accurate and closely follows the plan. We report our experience with the ArcCHECK phantom and investigate its potential optimization for the DQA process. One-hundred seventy DQA plans from 84 patients were studied. Plans were classified into 2 groups: those with the target situated on the diodes of the ArcCHECK (D plans) and those with the target situated at the center (C plans). Gamma pass rates for 8 target sites were examined. The parameters used to analyze the data included 3%/3 mm with the Van Dyk percent difference criteria (VD) on, 3%/3 mm with the VD off, 2%/2 mm with the VD on, and x/3 mm with the VD on and the percentage dosimetric agreement “x” for diode plans adjusted. D plans typically displayed maximum planned dose (MPD) on the cylindrical surface containing ArcCHECK diodes than center plans, resulting in inflated gamma pass rates. When this was taken into account by adjusting the percentage dosimetric agreement, C plans outperformed D plans by an average of 3.5%. ArcCHECK can streamline the DQA process, consuming less time and resources than radiographic films. It is unnecessary to generate 2 DQA plans for each patient; a single center plan will suffice. Six of 8 target sites consistently displayed pass rates well within our acceptance criteria; the lesser performance of head and neck and spinal sites can be attributed to marginally lower doses and increased high gradient of plans.

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

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

Phase I, Pharmacokinetic, and Pharmacodynamic Study of AMG 479, a Fully Human Monoclonal Antibody to Insulin-Like Growth Factor Receptor 1

To determine the maximum-tolerated dose (MTD) and to assess the safety, pharmacokinetics, and evidence of antitumor activity of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1 (IGF-1R). Patients with advanced solid malignancies or non-Hodgkin's lymphoma received escalating doses of AMG 479 intravenously (IV) every 2 weeks (Q2W). Blood samples were assayed to determine pharmacokinetic parameters and IGF-1R occupancy on neutrophils; fluorodeoxyglucose-positron emission tomography scans were used to assess tumor metabolic effects. Fifty-three patients received 312 infusions of AMG 479 Q2W. Overall, the most common grades 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. One dose-limiting toxicity (ie, grade 3 thrombocytopenia) occurred in a patient at 20 mg/kg during course 1; grade 3 thrombocytopenia (n = 8) and grade 3 transaminitis elevations (n = 1) also were reported but not in the escalation phase. The maximum-planned dose of 20 mg/kg was safely administered; thus, an MTD was not reached. High levels of neutrophil IGF-1R binding and increases from baseline in serum IGF-1 levels were observed in the 12- and 20-mg/kg cohorts. Tumor responses included one durable complete response (CR) and one unconfirmed partial response (PR) in two patients with Ewing/primitive neuroectodermal tumors and included one PR and one minor response in two patients with neuroendocrine tumors. The patients with Ewing/PNET who had a CR have remained disease free on therapy after 28 months. AMG 479 can be administered safely at 20 mg/kg IV Q2W. The absence of severe toxicities, attainment of serum concentrations associated with high levels of IGF-1R binding on neutrophils, and provocative antitumor activity warrant additional studies of this agent.