Phase I trial of fenretinide (4-HPR) intravenous emulsion for hematologic malignancies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 13007-13007 ◽  
Author(s):  
A. Mohrbacher ◽  
M. Gutierrez ◽  
A. J. Murgo ◽  
S. Kummar ◽  
C. P. Reynolds ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Emulsion Formulation ◽  
Steady State Levels ◽  
Relationship Of ◽  
Oral Capsule

13007 Background: 4-HPR is a retinoid cytotoxic for cancer cell lines. In clinical trials, oral capsule 4-HPR had limited bioavailability and activity. An intravenous intralipid emulsion formulation of 4-HPR (ILE 4-HPR) was developed to increase bioavailability. The objectives of this phase I trial were to determine a maximally tolerated dose (MTD) of ILE 4-HPR, and to assess toxicities, pharmacokinetics (PK), and preliminary response data. Methods: We used an accelerated titration Simon design 2 dose escalation schema with 100% increase in ILE 4-HPR per dose level tested until moderate toxicity was observed in 2 patients or DLT in one. Ten dose levels were planned with a starting dose of 80 mg/m2/day (continuous i.v. x 5 days q 3 weekly), increasing until Dose level 10 at 1,810 mg/m2. A De-escalation to 1,240 mg/m2/day Dose level 9 was added when DLT was observed in 2 patients at 1,810 mg/m2 dose level 10. Results: To date, 11 patients have been enrolled. At dose level 10 (1,810 mg/m2/day), 2 pts experienced a DLT of grade IV hypertriglyceridemia with grade 2 pancreatitis. A de-escalation to dose level 9 (1,280 mg/m2/day) has enrolled 4 pts, 1 had grade IV hypertriglyceridemia; enrollment is ongoing. We observed a transient response in a patient with NHL at 320 mg/m2 and a continued partial response in one patient with NHL on dose level 10 (1,810 mg/m2). PK showed a linear relationship of dose to plasma level, with steady-state levels of 54 μM (1,280 mg/m2)and 62 μM (1,810 mg/m2). Conclusions: ILE 4-HPR was given via continuous infusion to a dose of 1,810 mg/m2/day x 5 days. 1 patient with NHL had a transient partial response and a second patient with chemotherapy-refractory NHL had a partial response sustained on treatment for > 6 months. The DLT of hypertriglyceridemia is likely related to the intralipids delivered. Enrollment continues at a dose of 1,280 mg/m2/day. ILE 4- HPR can be safely administered and obtained plasma levels 6 to 7 times higher than previously obtained by oral capsule 4-HPR, with clinical activity in hematologic malignancies. No significant financial relationships to disclose.

Phase I Study of XK469R (NSC 698215), a Quinoxaline Phenoxypropionic Acid Derivative, in Patients with Refractory Hematological Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1952-1952
Author(s):  
Wendy Stock ◽  
Samir D. Undevia ◽  
Stefan Faderl ◽  
Olotoyosi Odenike ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Phase I ◽  
Acid Derivative ◽  
Dose Level ◽  
Phase I Study ◽  
Plasma Concentrations ◽  
Hematologic Malignancies ◽  
Median Number ◽  
Fixed Dose ◽  
Pharmacokinetic Analysis ◽  
Clinical Activity

Abstract XK469R is a quinoxaline phenoxypropionic acid derivative which possesses broad activity against murine and human tumors (including leukemia) and high activity against multidrug-resistant tumors. COMPARE analysis of cytotoxicity data from the NCI cell line screen suggested a unique mechanism. Phase I studies in patients with advanced solid tumors indicated that the dose-limiting toxicity (DLT) was myelosuppression, without other significant toxicities noted, at a fixed dose of 1400 mg/dose when given on a day 1,3,5 schedule every 21 days. Therefore, we conducted a phase I study to establish the DLT and maximally tolerated dose (MTD) of XK469R in patients with refractory hematologic malignancies, as well as to study the pharmacokinetics of XK469R in this patient population. XK469R was given as a straight dose as an IV infusion over 30 minutes-1 hour on days 1, 3, and 5 of a 21 day cycle. Because significant interpatient variability in drug clearance (associated with toxicity) was noted in prior studies, each dose cohort included a minimum of six patients. The dose levels studied were 1400 mg (n=6), 1750 mg (n=12), 2200 mg (n=14), and 2750mg (n=14). A total of 46 patients with relapsed/refractory leukemia have been treated and are evaluable for toxicity; 41 patients with AML, 4 ALL, and 1 CML-BC. The group consists of 26 males and 20 females with a median age of 53 (range 20–85). ECOG PS included 0 (n=19), 1 (n=21), and 2 (n=6). Median number of cycles received was 1; 10 patients received 2 cycles and 2 patients received 3 cycles. DLT was defined as any clinically significant grade 3 or 4 adverse nonhematologic toxicity other than prolonged myelosuppression, as defined by NCI criteria specific for leukemia. DLTs of colitis and mucositis were observed at the 2200 mg dose level, and mucositis and elevated bilirubin at the 2750 mg dose level. Other possibly related grade 1 and 2 toxicities noted were SGOT/PT elevations, nausea/vomiting, diarrhea, anorexia, indigestion, rash, and alopecia. The MTD, defined as the dose level at which <2/6 patients experience a DLT, was 2200 mg. Forty-two patients were evaluable for response and include CR (n=1, in 1750 mg cohort), HI (n=5), SD (n=21), and PD (n=15). Preliminary pharmacokinetic analysis revealed that plasma concentrations of XK469R decline in a biphasic manner. Half-life was long with a mean value of 48 h. Mean clearance was 206 ml/h with a coefficient of variation of 32%. Patients with lower clearance did not appear to be at greater risk of DLT. In conclusion, the recommended phase II dose of XK469R in patients with advanced leukemia is 1750 mg (day 1,3,5). Due to its novel mechanism of action, reasonable toxicity profile, and clinical activity in these high-risk patients, further exploration of XK469R, possibly in combination with other established agents, is warranted in patients with relapsed/refractory acute leukemia.

Phase I Trial of Fenretinide (4-HPR) Intravenous Emulsion for Hematologic Malignancies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2581-2581 ◽  
Author(s):  
Ann Mohrbacher ◽  
Martin Gutierrez ◽  
Anthony J. Murgo ◽  
Shivaani Kummar ◽  
C. Patrick Reynolds ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Level ◽  
High Performance ◽  
Dose Range ◽  
Systemic Exposure ◽  
Complete Response ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
T Cell Lymphomas ◽  
Oral Capsule

Abstract Background: 4-HPR is a cytotoxic retinoid with broad anti-cancer activity in preclinical studies, but oral capsule 4-HPR had limited bioavailability and activity in clinical trials. An intravenous intralipid emulsion formulation of 4-HPR (ILE 4-HPR) was developed to increase 4-HPR systemic exposure. Methods: ILE 4-HPR was administered as a continuous intravenous infusion for 5 of every 21 days and systemic toxicities, clinical response, and pharmacokinetics (PK) assessed. Simon design dose escalation proceeded with a 100% increase per dose level until moderate toxicity in 2 patients or 1 dose-limiting toxicity (DLT). Ten dose levels were planned starting at 80 mg/m2/day, increasing until 1810 mg/m2. Plasma 4-HPR levels were measured by high performance liquid chromatography. Results: To date, 17 patients have been enrolled. At dose level 10 (1810 mg/m2/day), 2 patients experienced a DLT of grade 4 hypertriglyceridemia, 1 patient with transient grade 2 pancreatitis. A de-escalation to dose level 9 (1280 mg/m2/day) enrolled 5 patients: 1 had asymptomatic Grade 4 hypertriglyceridemia, 1 patient experienced pleural effusions that resolved after pleurocentesis. A de-escalation to dose level 8 (905 mg/m2/day) enrolled 5 pts: two patients experienced asymptomatic Grade 4 hypertriglyceridemias that resolved after stopping the infusion; enrollment is ongoing. PK showed a linear relationship of dose to plasma level, with steady-state 4-HPR levels of 25 μM (640 mg/m2, level 7); 54 μM (1280 mg/m2, level 9) and 62 μM (1810 mg/m2, level 10). Responses to date include a transient response in a non-Hodgkins lymphoma at 320 mg/m2, in two angioimmunoblastic T-cell lymphomas, an 8-month partial response at 1810 mg/m2/day and a 4+ month unconfirmed complete response at 905 mg/m2/day, and in a histone deacetylase inhibitor-refractory cutaneous T cell lymphoma, a 10+ month molecular complete response at 1280 mg/m2. All patients were heavily pretreated. The DLT of hypertriglyceridemia is likely related to the intralipid formulation vehicle accounting for 5/6 DLTs observed, all reversible. Conclusions: ILE 4-HPR can be safely administered and obtained 4-HPR plasma levels 6 to 7 times higher than previously obtained by oral capsule 4-HPR. Durable clinical activity was observed in T cell lymphomas in the dose range 905–1810 mg/m2. Supported in part by NCI U01CA62505 and the NCI RAID program.

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

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 908-908 ◽  
Author(s):  
Karen W.L. Yee ◽  
Mark D. Minden ◽  
Joseph Brandwein ◽  
Aaron Schimmer ◽  
Andre Schuh ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Concurrent Schedule ◽  
Maximum Tolerated Dose ◽  
Leukemic Cells ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Sequential Schedule ◽  
Grade 3

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

KB004, a Novel Non-Fucosylated Humaneered® Antibody, Targeting EphA3, Is Active and Well Tolerated in a Phase I/II Study of Advanced Hematologic Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3756-3756 ◽  
Author(s):  
Ronan T Swords ◽  
Andrew H Wei ◽  
Simon Durrant ◽  
Anjali S. Advani ◽  
Mark S Hertzberg ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Bone Marrow Biopsies ◽  
Infusion Reactions ◽  
Equity Ownership ◽  
Dose Levels

Abstract Background: EphA3 is a novel drug target involved in cell positioning in fetal development. In adults it is an oncofetal antigen, that is re-expressed in hematologic malignancies (blood and bone marrow, leukemic stem cells) and solid tumors. It is also upregulated in diseases characterized by abnormal proliferation and fibrosis, such as idiopathic pulmonary fibrosis and diabetic kidney disease. KB004 is a Humaneered® high affinity antibody (KD = 610 pM) targeting EphA3 with at least 3 possible mechanisms of action: direct apoptosis in tumor cells, activation of ADCC and disruption of tumor vasculature. Objectives: The primary objectives of the Phase I study component are to determine safety and MTD for KB004 in patients with hematologic malignancies, refractory to or unfit for chemotherapy. Secondary objectives are to characterize PK, immunogenicity, and preliminary clinical activity of KB004. Exploratory objectives include evaluation of EphA3 expression on tumor, stromal, and endothelial cells. Methods: Multicenter Phase I/II study. Key eligibility criteria: unsuitable for standard of care or relapsed or refractory hematologic malignancy, ECOG PS 0-1, adequate organ function, platelets ≥ 10,000/uL (untransfused for 7 days) and normal coagulation times. KB004 was administered as a 1-2 hr intravenous infusion on days 1, 8, and 15 of each 21-day cycle, at incremental doses of 20, 40, 70, 100, 140, 190, 250 and 330 mg. At 70 mg and above infusion reaction prophylaxis included H1 and H2 blockers, acetaminophen and IV steroids. Safety and activity by IWG response criteria were assessed. Peripheral blood and bone marrow biopsies for PK analysis and EphA3 expression were also collected. Results: A total of 50 patients (AML 39, MDS 7, DLBCL 1, MF 3) received KB004 in the phase I/dose finding component of the study, which has been completed. The most common toxicities were transient grade 1 and grade 2 transient infusion reactions (IRs) in 79% of patients. IRs were characterized by chills, elevated temperature, fever, rigors, back pain, nausea, vomiting, hypotension, hypertension and transient hypoxia (in 2 cases). No other significant KB004 related toxicity was observed. Two patients discontinued KB004 due to an IR. One of these (grade 3) defined a DLT at the 330mg dose level. A second patient at 330mg had grade 2 infusion reactions associated with multiple infusion delays. These observations prompted expansion of the next lowest dose cohort, 250mg. Six evaluable patients were treated at this dose level. No clinically significant IRs or DLTs were observed. This is therefore the recommended phase 2 dose (RP2D). At all dose levels observed Cmax for KB004 was approximately dose proportional. Sustained exposure above the predicted effective concentration (1ug/mL) to cover the 7-day interval between doses was achieved above 190mg. Responses according to IWG criteria were observed in patients with AML, MF and MDS at the 20 mg, 140g and 250mg dose levels, respectively. At 20mg, a 78 yr-old patient with relapsed AML achieved CRp. Remission was sustained for over 18 months and relapse was preceded by a rise in EphA3 expression. Serial bone marrow biopsies with KB004 treatment show decreased reticulin and collagen fibrosis. At 140mg, a 67 yr old patient with JAK2 V617F mutant previously untreated myelofibrosis whose predominant clinical problem at diagnosis was anemia achieved Clinical Improvement [CI]. Transfusion independency (both RBC and platelets) has been sustained for 8+ months with improvement in constitutional symptoms and improved splenomegaly. At 250 mg an 84 yr-old patient with MDS/MPN (intermediate risk) achieved a Hematologic Improvement [HI, erythroid]. A > 50% reduction in marrow blast percentage was seen in 8 patients. Bone marrow biopsies positive for EphA3 expression with a cut-off of 10% of nucleated cells were obtained in greater than 70% of AML patients. Of 20 patients for whom EphA3 expression data exists with time, 7 (35%) had at least a 50% reduction in expression with treatment. Conclusion: KB004 is a novel agent targeted against EphA3 that is well tolerated when given as a weekly 2 hour infusion. The promising clinical activity profile is postulated to be consistent with the antifibrotic mechanism. The Phase II component of the study is ongoing in which the activity of KB004 will be characterized in disease specific cohorts including AML, MDS and MF at the RP2D of 250mg. Disclosures Durrant: KaloBios: Research Funding. Advani:KaloBios: Research Funding. Greenberg:Celgene: Research Funding; Novartis: Research Funding; GSK: Research Funding; Onconova: Research Funding; KaloBios: Research Funding. Cortes:KaloBios: Research Funding. Yarranton:KaloBios: Employment; Glaxo: Equity Ownership; EnGen: Equity Ownership, Science Advisor, Science Advisor Other; Stemline Therapeutics: Equity Ownership. Walling:KaloBios, Corcept Therapeutics, Prothena, NewGen Therapeutics, Valent Technologies, LBC Pharmaceuticals: Consultancy, Equity Ownership; Amgen, BioMarin: Equity Ownership; Crown BioScience: Membership on an entity's Board of Directors or advisory committees.

Fixed dose rate (FDR) gemcitabine (G) and capecitabine (C) in patients with advanced and/or metastatic cancer: phase I trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12016-12016
Author(s):  
D. Santini ◽  
B. Vincenzi ◽  
V. Virzì ◽  
A. La Cesa ◽  
G. Schiavon ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Rate ◽  
Cancer Patients ◽  
Dose Level ◽  
Phase I Trial ◽  
Metastatic Cancer ◽  
Fixed Dose ◽  
Clinical Activity ◽  
Open Label ◽  
Fixed Dose Rate

12016 Background: Combination of C and G has been demonstrated to be well tolerated, with apparent efficacy in patients with advanced cancers. To determine the toxicity of C plus Fixed Dose Rate (FDR) G in metastatic cancer patients, a phase I trial was conducted. Methods: This is an open-label, single-center, dose-escalating phase I study. C was administered orally according to the standard 21-day schedule: bid in equal doses (650 mg/m2 bid) for 14 days every 21 days. G was administered at a FDR of 10 mg/m2 per min in escalating durations of infusion on days 1 and 8 every 21 days. The doses of G explored were 600, 700, 800 mg/m2 infused at FDR in 60, 70 and 80 minutes, respectively. 15 pts (10 female, 5 male), aged 37–70 yr (median 66) with a variety of advanced solid tumors have been treated (11 peri-ampullary cancers, 3 colorectal cancers and 1 ovarian cancer). The FDR G dose was escalated when 3 patients in a cohort had completed two cycles of treatment without experiencing dose-limiting toxicities (DLT). The MTD was defined as the dose level at which no more than one of nine patients experienced a DLT. Results: No DLT occurred at doses of 600 and 700 mg/m2 in any of the 3 patients included at each level. At 800 mg/m2, 1 of 9 patients experienced DLT (neutropenia grade 4 with fever). The non-haematological toxicities have been generally mild or moderate in all patients (grade 2 stomatitis: 4 patients; grade 2 fatigue: 3 patients; grade 2 nausea/vomiting: 2 patients). 2 patients showed one episode of grade 4 neutropenia spontaneously regressed in 3 days. 2 patients showed one episode of grade 2 thrombocytopenia. The recommended dose for further studies is C bid in equal doses (650 mg/m2 bid) for 14 days (28 doses) plus FDR G at 800 mg/m2 infused in 80 minutes on days 1 and 8 every 21 days. Other patients with periampullary carcinoma are being evaluated at the same dose level, with an ongoing evaluation of cumulative (all cycles) toxicity and efficacy. In terms of response, we have observed 2 PR and 3 SD in the 6 pancreatic cancer patients evaluated for response after the first 3 cycles. Conclusions: C plus FDR G combination seems to be a feasible and safety approach which has demonstrated promising clinical activity. No significant financial relationships to disclose.

A Phase I/II Study of the Oral mTOR Inhibitor RAD001 in Patients with Advanced Hematologic Malignancies.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4818-4818
Author(s):  
Karen W.L. Yee ◽  
William Wierda ◽  
Susan O’Brien ◽  
Deborah Thomas ◽  
Razelle Kurzrock ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Human Cancer ◽  
Solid Organ Transplantation ◽  
Hematologic Malignancies ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Solid Organ ◽  
Extensive Experience ◽  
Transfusion Requirements

Abstract RAD001 (everolimus, Novartis) is an orally bioavailable derivative of rapamycin with demonstrated anti-proliferative activity against a broad panel of tumor cell lines and antitumor activity in experimental animal models of human cancer. RAD001 inhibits the mammalian target of rapamycin (mTOR) signaling pathway, which is involved in regulating many aspects of cell growth and cell cycle progression. Several lines of evidence implicate the importance of the PI3K/Akt/mTOR pathway in hematological malignancies. As there has been extensive experience with this agent in the solid organ transplantation setting, two dose levels (5 and 10 mg/day) were evaluated in the Phase I portion of this study to determine the maximum tolerated dose (MTD) to be used in the Phase II portion. RAD001 was administered orally once a day at the starting dose level of 5 mg. Fifteen patients have been enrolled, of which 14 (3 B-CLL, 4 MDS, 1 MF, 1 NK/T cell lymphoma/leukemia, 1 MCL, 3 AML, 1 T-PLL) were evaluable for safety and toxicity. Median age was 65 years (range, 56 to 76 years). Twelve patients (86%) had received prior therapy (median, 2 regimens; range, 0 to 6 regimens). Median time on study was 29 days (range, 12 to 105 days). No dose-limiting toxicities were observed in the 6 patients enrolled in the Phase I portion of the study (cohorts of 3 patients per dose level). The most common adverse events were grade ≥ 2 and consisted of hyperglycemia, hyperlipidemia, hypocalcemia, hypomagnesemia, hypophosphatemia and hypokalemia, transaminitis, diarrhea, dermatitis, and mucositis. Grade 3 toxicities consisted of asymptomatic hypophosphatemia (2), and hyperglycemia (3). No patient experienced grade 4 toxicities or death from RAD001. Of the 14 evaluable patients, 2 patients with B-CLL had a 33% and 65% reduction in the size of lymph nodes, respectively, and 1 patient with MDS had decreased transfusion requirements. At the time of analysis, only 1 patient had discontinued therapy due to disease progression. These preliminary findings indicate that RAD001 is well tolerated at a daily dose of 10 mg/day and may have clinical activity in patients with hematologic malignancies. Enrollment is ongoing.

Phase I Study of Lorvotuzumab Mertansine (IMGN901) In Combination with Lenalidomide and Dexamethasone In Patients with CD56-Positive Relapsed or Relapsed/Refractory Mulitple Myeloma - A Preliminary Safety and Efficacy Analysis of the Combination

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1934-1934 ◽  
Author(s):  
Jesus G Berdeja ◽  
Sikander Ailawadhi ◽  
Ruben Niesvizky ◽  
Jeffrey L Wolf ◽  
Sybil H Zildjian ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Single Agent ◽  
The Other ◽  
Clinical Activity ◽  
Serious Adverse Events ◽  
Dose Cohort ◽  
Objective Evidence

Abstract Abstract 1934 Background: Lorvotuzumab mertansine, also known as IMGN901 (huN901-DM1/BB-10901) is a novel anticancer agent consisting of a potent cytotoxic maytansinoid, DM1, attached to a CD56-binding monoclonal antibody, lorvotuzumab, using an engineered disulfide linker. Once bound to CD56 on a cancer cell and internalized, the conjugate releases DM1. About 78% of multiple myeloma (MM) cases have strong surface expression of CD56. In preclinical settings, IMGN901 showed significant in vitro and in vivo anti-myeloma activity as a single agent and in combination with approved drugs such as lenalidomide. IMGN901 has also been shown to be active and well tolerated as a single agent in a separate phase I study in patients with relapsed or relapsed/refractory MM. Objectives: To determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT), pharmacokinetics (PK), and activity of IMGN901 in combination with lenalidomide and dexamethasone in patients with MM. Methods: Patients with CD56+ relapsed or relapsed/refractory MM receive IMGN901once weekly for 3 consecutive weeks every 4 weeks (Days 1, 8, 15 every 28 days). Lenalidomide (25mg) is taken orally once daily on Days 1 to 21 every 28 days and dexamethasone (40mg) is taken orally once weekly for 4 weeks (Days 1, 8, 15, and 22 every 28 days). The doses of lenalidomide and dexamethasone will remain fixed while escalating dose levels of IMGN901 are assessed. Patients are enrolled into each dose level in cohorts of 3, with DLTs triggering cohort expansion. Pharmacokinetics of IMGN901 and lenalidomide at the MTD will be collected, with exploratory pharmacodynamic studies planned. Results: The first dose cohort (75mg/m2 IMGN901) has been fully enrolled and accrual to the second dose cohort (90mg/m2) has commenced. There has been no DLT, no serious adverse events, and no drug-related grade 3 or 4 toxicities. Among the three patients enrolled in the 75mg/m2 dose cohort, by the end of cycle 2, one withdrew secondary to progressive disease (PD) and the other two had achieved a partial response (PR) based on the International Uniform Response Criteria for MM; the two patients with PRs remain on study. One of these patients had received 3 prior lines of therapy plus a transplant. This patient's PR has since improved to a very good partial response (as of end of Cycle 3). The other responding patient had received 4 prior treatment regimens plus 2 transplants. Conclusions: In this assessment of IMGN901 used in combination with lenalidomide and dexamethasone in patients with CD56+ relapsed or relapsed/refractory MM, objective evidence of clinical activity has been observed in two of the three patients who received the first dose level of IMGN901 evaluated. The combination has been well tolerated to date, MTD has not been defined and dose escalation continues. This very early experience is encouraging and supports the continued assessment of IMGN901 used in combination with lenalidomide and dexamethasone for patients with CD56+ relapsed or relapsed/refractory MM. Disclosures: Ailawadhi: Celgene: Speakers Bureau. Zildjian:ImmunoGen, Inc.: Employment. O'Leary:ImmunoGen, Inc.: Employment.

Combination of Bendamustine, Lenalidomide, and Dexamethasone In Patients with Refractory or Relapsed Multiple Myeloma Is Safe and Highly Effective: Results of a Phase I Clinical Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 989-989
Author(s):  
Suzanne Lentzsch ◽  
Amy O'Sullivan ◽  
Ryan Kennedy ◽  
Navkiranjit Gill ◽  
Carrie Andreas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Phase I Trial ◽  
Clinical Activity ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Level 2

Abstract Abstract 989 Background: Lenalidomide is an analog of thalidomide that has significant clinical activity in combination with dexamethasone in patients with relapsed or refractory multiple myeloma (MM). Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. This multicenter phase I trial is the first to investigate the combination of bendamustine, lenalidomide, and dexamethasone. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods: Patients aged ≥18 years with confirmed, measurable symptomatic MM that was refractory to or progressed after 1 or more prior therapies were treated with bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau or best response, as determined by the International Myeloma Working Group uniform response criteria, was reached. Study drug doses were escalated through 3 levels (Table 1) in a 3+3 dose-escalation scheme. The MTD was defined as the dose level at which ≤1 of 6 patients experienced dose-limiting toxicity (DLT) during the first cycle of therapy when the next higher dose level is associated with DLTs in ≥2 patients. After determining the MTD, an expansion cohort of 12 additional patients at the MTD will be treated to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy as evidenced by objective response, time to disease progression, and overall survival. Results: Twenty-six patients with a median age of 63 years (range, 38 to 81 years) were enrolled. The mean number of prior therapies was 3 (range, 2–7); 81% of the patients had prior lenalidomide, 48% had prior thalidomide, and 29% had both. The MTD was identified at dose level 2: 75 mg/m2 bendamustine and 10 mg lenalidomide. Four DLTs were recorded: at dose level 2 (n = 6), 1 patient with grade 4 neutropenia; at dose level 3 (n = 6), 2 patients with grade 4 neutropenia and another with delayed platelet recovery from grade 3 thrombocytopenia. Currently 9 patients have been enrolled in the expansion cohort. Twenty-one of 26 patients received at least 2 cycles and were included in the response assessment. A partial response (PR) or better was observed in 63% (n = 12) of the patients, including 16% (n = 3) achieving a very good PR (VGPR). In addition to these 12 patients, another 3 (15%) had a minor response (25%-49% reduction in M-protein). Stable disease was observed in 32% (n = 6), and only 5% (n = 1) had disease progression. The median time to next treatment was 8.1 months (range, 1.9–27.3 months). Other grade 3/4 adverse events occurring after the first cycles of treatment included prolonged QTc in 1 patient. Conclusions: This is the first phase I trial testing the combination of bendamustine, lenalidomide, and dexamethasone for relapsed and refractory MM. This regimen is well tolerated even in older patients up to 81 years. With a PR/VGPR rate of 63%, this combination is a highly active regimen even in heavily pretreated MM patients, and its side effect profile makes it an attractive treatment option for MM patients especially with pre-existing therapy-related peripheral sensory neuropathy. Final data on response and overall survival will be available at the time of presentation. Disclosures: Lentzsch: Celgene Corp: Research Funding. Roodman:Amgen, Novartis, Celgene, Acceleron: Consultancy. Zonder:Amgen, Celgene, Cephalon: Consultancy; Millennium: Research Funding; Millennium: CME only, no promotional work.

Phase I trial of the somatostatin analog octreotide acetate in the treatment of fluoropyrimidine-induced diarrhea.

1995 ◽  
Vol 13 (1) ◽  
pp. 222-226 ◽  
Author(s):  
S Wadler ◽  
H Haynes ◽  
P H Wiernik
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Response To Therapy ◽  
Somatostatin Analog ◽  
Watery Diarrhea ◽  
Gastrointestinal Malignancies ◽  
Octreotide Acetate

PURPOSE Diarrhea is one of the dose-limiting toxicities for administration of fluorouracil (5FU) in patients with gastrointestinal malignancies and can result in severe morbidities or mortality. The somatostatin analog octreotide acetate has been used in the treatment of 5FU-induced diarrhea with promising results. A phase I trial was initiated to determine the maximum-tolerated dose of octreotide acetate that could be administered in this setting. PATIENTS AND METHODS Patients were required to have National Cancer Institute Common Toxicity Criteria > or = grade 2 diarrhea or watery diarrhea secondary to treatment with 5FU or a modulated 5FU regimen. At least three patients were treated at each dose level; after satisfactory completion of this dose level (zero of three or one of six patients with < or = grade 2 toxicity), additional patients were added at the next dose level. Doses of octreotide acetate studied were 50 to 2,500 micrograms subcutaneously three times daily for 5 days. RESULTS A total of 35 patients received 49 courses of therapy. The only significant toxicities occurred at 2,500 micrograms. At this dose level, one patient developed an allergic reaction with flushing, nausea, and dizziness after each of the first two injections. A second patient developed asymptomatic hypoglycemia with a serum glucose level of 26 mg/dL. The maximum-tolerated dose was 2,000 micrograms. The efficacy of the treatment correlated significantly (P = .01) with the dose of octreotide administered, and more patients completed the course of therapy at the higher doses. CONCLUSION Octreotide acetate can be safely administered for the treatment of fluoropyrimidine-induced diarrhea in patients with gastrointestinal malignancies. The dose-limiting toxicities were allergic (nausea, rash, and light-headedness) and endocrine (hypoglycemia). There was a significant correlation between complete response to therapy and octreotide dose.

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