MM-008 trial: Pharmacokinetics (PK) and tolerability of pomalidomide plus low-dose dexamethasone (POM plus LoDEX) in relapsed/refractory multiple myeloma (RRMM) patients with renal impairment (RI).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8585-8585
Author(s):  
Jeffrey Matous ◽  
David Samuel DiCapua Siegel ◽  
Hien Kim Duong ◽  
Claudia Kasserra ◽  
Lars Sternas ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Dose Escalation ◽  
Drug Exposure ◽  
Severe Renal Impairment ◽  
Phase 1 ◽  
Parent Drug ◽  
Clinical Activity ◽  
Open Label ◽  
Grade 3

8585^ Background: POM + LoDEX has shown significant clinical activity in RRMM pts including those refractory to lenalidomide and bortezomib. Renal impairment is a common comorbidity for MM pts, occurring in > 40%. POM is extensively metabolized with less than 5% renally eliminated as parent drug. Thus, renal function may not substantively affect parent drug exposure. Previous POM trials excluded pts with severe renal impairment. MM-008 is a phase 1, multicenter, open-label study designed to assess the PK and safety of POM + LoDEX in RRMM pts and normal or impaired renal function. Methods: RRMM pts (≥ 1 prior therapy [Tx]) with creatinine clearance (CrCl) ≥ 60 ml/min (cohort A) or severe renal impairment (CrCl < 30 ml/min [cohort B]) not requiring dialysis were included. Cohort A received POM 4 mg and cohort B received POM 2 mg or 4 mg D1-21/28-day cycle following a standard 3 + 3 dose-escalation design. Both cohorts received DEX 40 mg (20 mg for pts aged > 75 y) D1, 8, 15, and 22. Cohort C will assess pts with severe renal impairment (CrCl < 30 ml/min) requiring dialysis (up to 14 pts planned). Pts were not permitted to enroll in more than 1 cohort. G-CSF was not permitted in cycle 1. Tx continued until progressive disease or unacceptable toxicity. Results: As of Feb 5, 2013, 11 pts have been treated (8 pts in cohort A; 3 pts in cohort B at 2 mg). Age ranged from 46-71 y (cohort A) and 57-64 (cohort B). 5 pts were aged > 65 y in cohort A (aged 66, 69 [n = 3], and 71 y); none in cohort B. 7 pts in cohort A have received > 1 cycle of Tx; 5 pts have received ≥ 3 cycles. One pt in cohort B has received > 3 cycles. All 3 pts in cohort B have completed 1 full cycle of Tx with no dose-limiting toxicities reported. Dose escalation is planned. The most common grade 3/4 adverse events (AEs) in cohort A were neutropenia (n = 3) and pneumonia (n = 2). No grade 3/4 AEs have been observed for pts in cohort B to date. POM dose reduction due to AE occurred in 2 pts (both in cohort A), all pts remain on study. PK and updated AE data will be presented at the meeting. Conclusions: MM-008 is an ongoing trial evaluating PK and safety in pts with renal impairment. Early tolerability data are encouraging. Clinical trial information: NCT01575925.

Safety, Tolerability, and Pharmacology of Bortezomib in Cancer Patients with Renal Failure Requiring Dialysis: Results from a Prospective Phase 1 Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3477-3477 ◽  
Author(s):  
Daniel Mulkerin ◽  
Scot Remick ◽  
Chris Takimoto ◽  
Percy Ivy ◽  
Michael Karol ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Dose Escalation ◽  
Severe Renal Impairment ◽  
Phase 1 ◽  
Case Series ◽  
Sensory Neuropathy ◽  
Red Blood Cell Transfusion ◽  
Hematologic Toxicity ◽  
Severe Impairment ◽  
Grade 3

Abstract Background: Bortezomib (btz; VELCADE®) is a specific, reversible proteasome inhibitor approved for the treatment of patients (pts) with multiple myeloma (MM) and mantle cell lymphoma following at least one prior therapy. Retrospective analyses of phase 2/3 studies and case series have shown btz alone or in combination is active and tolerable in MM pts with various degrees of renal impairment, including pts on dialysis. We previously reported clinical and pharmacologic data from the first prospective, dose-escalating study of btz in adult cancer pts with various degrees of renal impairment (ASCO 2006, abstract 2032). Here we present updated safety and tolerability data for dialysis-dependent patients. Methods: Pts with advanced cancer were stratified by renal function into controls and four groups ranging from mild impairment to dialysis dependence. Pts received btz on d 1, 4, 8, and 11 of a 21-day cycle; dose escalation (0.7, 1.0, 1.3 mg/m2) proceeded in cohorts of 3 pts based on dose limiting toxicities (DLTs) observed in cycle 1. Blood samples were taken on d 1 and 8 of cycle 1 for pharmacokinetic (PK) and pharmacodynamic (PD) analysis. Adverse events (AEs) were evaluated using NCI CTC v2.0. DLTs were grade 4 neutropenia for ≥7 d or neutropenic fever, grade 4 thrombocytopenia for ≥7 d, grade 4 hemoglobin for ≥7 d, and grade ≥3 non-hematologic toxicity. Results: To date, 59 pts have been treated, including 16 controls, 34 pts with mild-to-severe impairment, and 9 dialysis pts. Among dialysis pts: 3 were treated at 0.7, 2 at 1.0, and 4 at 1.3 mg/m2; median age was 62 y (range: 42–74); tumor types were MM (n=4), follicular lymphoma (n=1), and solid tumors (n=4). Median number of treatment cycles received was 2 in controls and across renal impairment groups. Dialysis pts received a median of 2 treatment cycles (range: 1–4); 1 pt remains on therapy. Dose escalation was well tolerated, with no DLTs, in pts with mild-to-severe renal impairment. There were no DLTs in cycle 1 in dialysis pts. Toxicities were generally mild in all groups. Among dialysis pts, no unexpected toxicities were seen. One grade 4 treatment-related AE (elevated creatinine) has been reported; grade 3 treatment-related AEs include platelets/thrombocytopenia (3 pts), diarrhea, hemoglobin, leukopenia, lymphopenia, packed red blood cell transfusion, sensory neuropathy, and vomiting (1 pt each). The overall AE profile in dialysis pts was similar to that in controls and in pts with mild-to-severe impairment, although renal and metabolic AEs appeared more common in dialysis pts. Conclusions: Btz at doses up to 1.3 mg/m2 on this schedule was well tolerated in pts with advanced malignancies with mild-to-severe renal impairment and dialysis dependence. PK and PD analyses for dialysis pts treated at 1.3 mg/m2 will be reported. Btz is a viable treatment option for pts requiring dialysis.

A Phase 1 Study of Sequential Idarubicin + Cytarabine, Followed by Lenalidomide, in Patients with Previously Untreated Acute Myeloid Leukemia (AML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2600-2600 ◽  
Author(s):  
Jeffrey E. Lancet ◽  
Rami S. Komrokji ◽  
Daohai Yu ◽  
Anjali S. Advani ◽  
Tammy Searles ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Survival Data ◽  
Research Funding ◽  
Drug Exposure ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Open Label ◽  
Phase 1 Study ◽  
Simultaneous Exposure

Abstract Abstract 2600 Background: Lenalidomide (Len) is an immunodulatory agent with proven efficacy in lower-risk myelodysplastic syndromes (MDS) and with strong signals of single-agent activity in higher-risk MDS and AML patients (pts). Our preclinical data showed that Len antagonized cytarabine cytotoxicity with simultaneous exposure, while augmenting the effects of anthracyclines and cytarabine with sequential drug exposure. We initiated a phase 1 combination study in patients with AML investigating sequential standard induction chemotherapy followed by Len. Objectives: 1) to determine the safety and maximum tolerated dose (MTD) of Len following idarubicin/cytarabine induction. 2) to assess preliminary signs of efficacy of this regimen in adults with previously untreated AML. Methods: This was a multicenter, open-label, dose escalation phase 1 study with a 3+3 dosing design of idarubicin (12 mg/m2, day 1–3), cytarabine (100 mg/m2, CI day 1–7) + Len (starting dose 5 mg, day 8–21). Len dose was escalated in 5 mg increments up to a maximum of 25 mg/day. Eligibility included pts with AML age ≥60 years or age <60 with associated del 5/5q; or MDS/RAEB-2 with prior hypomethylating agent failure. Other inclusion criteria included: ECOG PS 0–2 and adequate end-organ function (including normal LVEF of ≥ 50%). Pts who achieved CR/CRi after 1 or 2 cycles of induction were eligible to receive post-remission idarubicin/cytarabine/Len (at the same dose level) for up to 2 cycles, followed by Len maintenance 10 mg/day for up to 12 months. The MTD cohort was expanded to 10 patients. Results: Of 23 enrolled and treated pts, 21 have completed at least 1 treatment cycle. Median age was 68 years (range 44–79); males: 18 (78%). Eleven pts had del 5/5q associated karyotype (10 of whom had complex karyotype), and 15 had secondary AML (including 8 who received prior hypomethylating agents). Len dose escalation reached 25mg/day, with MTD determined to be 20 mg/day. Dose-limiting toxicities occurred in 2 of 3 patients treated at Len 25 mg/day (grade 3 rash; grade 4 neutropenia and thrombocytopenia persisting beyond day 56) and in 1 of 8 patients treated at Len 20 mg/day (grade 4 cardiac ischemia). Only 1 of 21 (5%) patients died within 30 days of treatment initiation. The most common therapy-related non-hematologic toxicities (occurring in ≥ 20% of patients, the vast majority of which were grade 1–2) included: diarrhea (76%), infection/febrile neutropenia (71%), rash (62%), nausea (43%), pain (43%), hemorrhage (33%), fatigue (29%), and non-neutropenic fever (24%). Of the 20 patients evaluable for response, 7 achieved CR and 1 CRi, for an overall response rate (ORR) of 40%. Of 11 evaluable patients treated at the MTD (Len 20 mg/day) and higher, the ORR was 55%. CR occurred in 3 out of 10 (30%) patients with associated del 5/5q. Conclusion: Sequential idarubicin/cytarabine + Len was generally well-tolerated in a primarily older population of patients with previously untreated AML, with MTD of 20 mg/day for Len. Clinical activity in this poor-risk population appears promising at the MTD and higher. Further exploration of this regimen in older AML patients is warranted, with plans for a phase 2 expansion underway. Updated toxicity, response, and survival data will be presented. Disclosures: Lancet: Celgene: Research Funding. Off Label Use: Lenalidomide is approved for use in MDS. Its investigational role in AML will be discussed. Komrokji:Celgene: Honoraria, Research Funding, Speakers Bureau. Sekeres:Celgene: Advisory Board. List:Celgene: Consultancy.

scholarly journals An Open-Label, Phase 1 Study Evaluating the Safety and Pharmacokinetics of Pralatrexate in Relapsed/Refractory Advanced Solid Tumors or Advanced Lymphoma/Myeloma Patients with Mild, Moderate, and Severe Renal Impairment

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3966-3966
Author(s):  
Kevin R. Kelly ◽  
Nashat Y. Gabrail ◽  
William J Edenfield ◽  
A Craig Lockhart ◽  
Anthony J. Olszanski ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Solid Tumors ◽  
Normal Renal Function ◽  
Severe Renal Impairment ◽  
Phase 1 ◽  
Moderate Renal Impairment ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1 Study

Abstract Introduction: Pralatrexate is a folate analogue indicated for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) that is preferentially taken up in cancer cells through the reduced folate carrier. While 34% of pralatrexate is excreted unchanged in the urine following a single, 30 mg/m2 dose administered as an IV push, a population PK analysis showed that drug clearance decreased with decreasing creatinine clearance. In addition, methotrexate, also a folate analogue, does need to be dose-reduced for patients with moderate or severe renal impairment. Pralatrexate, however, has not been formally tested in patients with renal impairment, and previous studies excluded patients with severe renal impairment. This study was, therefore, conducted to determine the need for pralatrexate dosing adjustments in patients with renal impairment. Methods: This was an open label, nonrandomized, Phase 1 study to determine the PK profile of pralatrexate in patients with relapsed/refractory advanced solid tumors or advanced lymphoma/myeloma with renal impairment. Primary objective of the study was to establish dosing recommendation of pralatrexate in renally compromised patients and to determine the pharmacokinetic profile in these patients. Four cohorts (n=6 per cohort) were planned to be enrolled in this study for a total of 24 patients. Patients with normal renal function (eGFR ≥90 mL/min/1.73 m2, Cohort A), mild (eGFR= 60 to <90 mL/min/1.73 m2, Cohort B) and moderate renal function (eGFR = 30 to < 60 mL/min/1.73 m2, Cohort C) were dosed with 30 mg/m2 pralatrexate once weekly for 6-weeks in a 7-week cycle. The pralatrexate dose was empirically reduced to 20 mg/m2 in patients with severe renal impairment (eGFR = 15 to < 30 mL/min/1.73 m2, Cohort D). Plasma and urine samples were collected at pre-specified time points to determine the PK profile. Patients who continued treatment with pralatrexate were then followed for safety and tolerability. Results: A total of 29 patients (14 male and 13 female) were enrolled in the study with 6 patients in each cohort. There were slightly more male patients (n=14, 52%) than female patients (n=13, 48%) enrolled; fewer males (33%) were in the mild renal impairment group and more males (83%) were in the moderate renal impairment group. The median age was 62.0 years. The majority of patients were White (n=22, 81%); the remaining patients were Black (n=5, 19%). Because of a qualifying toxicity in Cohort C, the starting dose was reduced to 15 mg/m2 in Cohort D. The major effect of chronic renal impairment was to decrease renal clearance of the pralatrexate diastereomers, PDX-10a and PDX-10b, but systemic exposure to these diastereomers was not dramatically affected by renal impairment. Mean total exposures of PDX-10a and PDX-10b were comparable across cohorts, including Cohort D. The empiric dose reduction to 15 mg/m2 in Cohort D was able to match the average exposures for Cohort A (with normal dose of 30 mg/m2). Although Cohorts B and C had elevated mean exposures and higher inter-patient variability than Cohorts A and D, it appears to be a result of non-renal factors. In summary, total exposures of PDX-10a and PDX-10b after a single IV injection of racemic pralatrexate are not dramatically affected by renal impairment. There was no apparent difference in either the incidence or types of TEAEs between the four treatment cohorts, and, therefore, the safety of pralatrexate was not affected by differences in renal function. The most common treatment related AEs were stomatitis (n=23, 83%), nausea (n=10, 37%), anemia (n=7, 26%) and fatigue (n=6, 22%). Conclusion: The pralatrexate exposure in patients with mild or moderate renal impairment is similar to the patients with normal renal function at a dose of 30 mg/m2. For patients with severe renal impairment, a pralatrexate dose of 15 mg/m2 is recommended. Disclosures Gabrail: Sanofi: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; Onyx: Honoraria, Speakers Bureau; BI: Honoraria, Speakers Bureau. Edenfield:Celgene: Research Funding. Reddy:spectrum: Employment, Equity Ownership.

A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-1287 administered daily to patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3611-3611
Author(s):  
Ben George ◽  
Donald A. Richards ◽  
William Jeffery Edenfield ◽  
Steven L Warner ◽  
Lars Mouritsen ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3

3611 Background: TP-1287 is a an orally bioavailable phosphate prodrug of alvocidib, a cyclin dependent kinase 9 (CDK9) inhibitor. TP-1287 exhibits potent inhibition of intracellular kinases including CDK9. Inhibition of CDK9 leads to downregulation of the BCL-2 family member, MCL-1, which in turn inhibits tumor growth in preclinical animal models of prostate, breast, and lung carcinomas. Methods: This is a multicenter, Phase 1, dose escalation study using a standard 3+3 design with a modified Fibonacci scheme to examine the safety and clinical activity of TP-1287 in patients with advanced solid tumors. Patients will be added at the maximum tolerated dose (i.e. expansion cohort) to test TP-1287 as a single agent in patients with castrate resistant prostate cancer. Results: Twenty-two patients who were enrolled between December 2018 and January 2020 received a range of doses from 1 mg QD to 11 mg BID over 7 cohorts. Data are available for 20 patients as of the data cutoff date. TP-1287 plasma PK Cmax and AUC increased in near linear fashion over cohorts 1 thru 6, reaching 80 ng/mL and 499.3 ng*h/mL in cohort 6 for Cmax and AUC, respectively. TP-1287 treatment resulted in dose-dependent reductions of phospho-RNA Pol II, consistent with CDK9 inhibition, as measured by a flow cytometric assay assessing pharmacodynamic changes in phosphorylation state in PBMCs. The most frequently observed Grade 3 AE was unrelated anemia in 2 patients. All other events of Grade 3 (9 events/7 patients) and Grade 4 (1 event/seizure with new CNS mets) were unlikely related or unrelated. Clinical benefit was seen in one sarcoma patient with PR (15+cycles), one RCC patient with SD (7+cycles) and 2 bladder cancer patients with SD (6 and 8 cycles). Conclusions: These findings suggest that TP-1287 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, refractory solid tumors and further clinical development in selected indications is warranted. Clinical trial information: NCT03298984 .

scholarly journals A Phase 1 Study To Assess the Pharmacokinetics of Intravenous Plazomicin in Adult Subjects with Varying Degrees of Renal Function

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
Allison S. Komirenko ◽  
Valerie Riddle ◽  
Jacqueline A. Gibbons ◽  
Scott Van Wart ◽  
Julie D. Seroogy
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Normal Renal Function ◽  
Severe Renal Impairment ◽  
Phase 1 ◽  
Open Label ◽  
Time Curve ◽  
Open Label Study ◽  
Severe Impairment ◽  
Tract Infections

ABSTRACTPlazomicin is an FDA-approved aminoglycoside for the treatment of complicated urinary tract infections. In this open-label study, 24 adults with normal renal function or mild, moderate, or severe renal impairment (n= 6 per group) received a single 7.5-mg/kg of body weight dose of plazomicin as a 30-min intravenous infusion. Total clearance declined with renal impairment, resulting in 1.98-fold and 4.42-fold higher plazomicin exposures, as measured by the area under the concentration-time curve from 0 h to infinity, in subjects with moderate and severe impairment, respectively, than in subjects with normal renal function. (This study has been registered at ClinicalTrials.gov under identifier NCT01462136.)

Clinical Activity of the Immunoconjugate CMC-544 in B-Cell Malignancies: Preliminary Report of the Expanded Maximum Tolerated Dose (MTD) Cohort of a Phase 1 Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2711-2711 ◽  
Author(s):  
Luis Fayad ◽  
Hemant Patel ◽  
Gregor Verhoef ◽  
Myron Czuczman ◽  
James Foran ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Remission Rate ◽  
International Workshop ◽  
Phase 1 ◽  
Objective Response ◽  
Safety Data ◽  
Clinical Activity ◽  
B Cell Lymphomas ◽  
Grade 3

Abstract Introduction: CMC-544 is an antibody-targeted chemotherapy agent composed of a humanized antibody that specifically targets the CD22 antigen, conjugated to calicheamicin, a potent cytotoxic antitumor agent. Malignant cells of mature B-lymphocyte lineage express CD22, suggesting that CMC-544 may be useful for treating lymphomas of B-cell origin. A phase 1 dose-escalation trial of CMC-544 was performed at 14 European and US sites with 36 patients in the dose escalation portion and 48 in the expanded MTD portion. The MTD dose was 1.8 mg/m2 every 4 weeks. In the dose escalation phase the main toxicities observed were thrombocytopenia, asthenia, nausea, neutropenia, elevated liver function tests (LFTs) and anorexia. Grade 3–4 levels were only seen for thrombocytopenia, asthenia, neutropenia and LFTs (incidence of 40%, 13%, 9% and 9% respectively). Responses were seen in 8/22 (36%) patients (Advani A, et. al. Blood, abstract# 230, 2005:106). We now report the results of the expanded cohort at the MTD. Patients and Methods: Relapsed/refractory lymphoma patients were treated at the 1.8 mg/m2 dose level every 4 weeks. In addition to safety data, preliminary efficacy data (assessed using the International Workshop to Standardize Response Criteria for NHL) were collected. Results: As of July 2006, 48 patients were treated: median age 57 years (range 26–75); 51% females; 61% with ≥ 4 prior lines of therapy; 22 (46%) follicular lymphomas (FL) and 26 (54%) diffuse large B-cell lymphomas (DLBCL). Data were available on 48 patients evaluable for safety and 34 patients (19 FL and 15 DLBCL) evaluable for response. The overall safety profile was manageable; the most common drug-related adverse events (all grades) included thrombocytopenia (90%; the only bleeding noted was grade 1–2 epistaxis [12%]), asthenia (57%), nausea (39%), neutropenia (37%) and elevated levels of AST/SGOT (41%), ALT/SGPT (18%), alkaline phosphatase (27%) and bilirubin (18%). Grade 3–4 AEs that occurred with a frequency ≥ 10% included thrombocytopenia (57%) and neutropenia (29%). Responses in evaluable patients are shown in Table 1. The objective response rate was 69% and 33% for patients with FL and DLBCL, respectively. Conclusions: CMC-544 exhibits effficacy against recurrent/refractory B-cell lymphomas, with the main toxicity being clinically manageable, self limited thrombocytopenia. These encouraging data support the continuing development of CMC-544. Number (%) of Responses in Evaluable Patients: Response Follicular Lymphoma (n=19) DLBCL (n=15) ORR = Overall Remission Rate, (CR/CRu+PR) CR/CRu 6 (31.7) 2 (13.3) PR 7 (36.8) 3 (20.0) ORR 13 (68.5) 5 (33.3)

Preliminary Results from a Phase 1/2, Open-Label, Dose-Escalation Clinical Trial of IMO-8400 in Patients with Relapsed or Refractory Waldenstrom's Macroglobulinemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1540-1540 ◽  
Author(s):  
Sheeba K. Thomas ◽  
Wael A. Harb ◽  
Joseph Thaddeus Beck ◽  
Gabrail Nashat ◽  
M. Lia Palomba ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Open Label ◽  
Label Dose ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p

Abstract Introduction: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by lymphoplasmacytic cell infiltration of bone marrow and elevated serum levels of immunoglobulin M (IgM) protein. Despite recent advances in treatment the disease relapses in most patients. About 90% of WM patients harbor the MYD88 L265P oncogenic mutation. MYD88 is an adapter protein in the Toll-like receptor (TLR) pathway. The MYD88 L265P oncoprotein has been shown to amplify TLR 7 and 9 signaling, leading to downstream activation of NF-κB and cytokine signaling pathways that promote tumor cell survival and proliferation (Lim, AACR 2013). IMO-8400 is an investigational oligonucleotide antagonist of endosomal TLRs 7, 8 and 9. In preclinical studies in a human cell line and animal models of WM, IMO-8400 inhibited key cell signaling pathways, including NF-κB, BTK, STAT-3 and IRAK-4, and inhibited tumor growth and tumor IgM production. In Phase 1 and 2 clinical trials in healthy subjects (N=30) and in patients with autoimmune disease (N=35), IMO-8400 was generally well tolerated and demonstrated evidence of clinical activity. Based on these data, we initiated a Phase 1/2 clinical trial of IMO-8400 in WM, the first study of a drug candidate specifically targeting the MYD88 L265P mutation. Methods: This Phase 1/2 multicenter, open-label, dose-escalation clinical trial continues to recruit adult patients with relapsed or refractory WM (NCT Identifier: NCT02092909). In a classic 3x3 dose escalation scheme, patients are enrolled in one of three sequential escalating dose cohorts and receive subcutaneous IMO-8400 at dosages of 0.6, 1.2 or 2.4 mg/kg per week, respectively, for 24 weeks. The presence of the MYD88 L265P mutation is assessed by PCR-based genetic screening following enrollment. Patients who complete the 24-week treatment period are eligible to enroll in an extension trial. The primary study objective is to evaluate the safety and tolerability of escalating IMO-8400 dosages. Secondary objectives include preliminary evaluation of clinical response based on international guidelines and identification of an optimal dose for further evaluation (Kimby, Clin Lymphoma Myeloma 2006). Results: Overall, 17 patients (6 female, 11 male) have been enrolled in three dose cohorts to date. Median baseline characteristics include: age 66 years, prior therapies 4 (range 1-13), serum IgM 2,225 mg/dL, serum M protein 0.96 g/dL, and B2-microglobulin 3.42 mg/L. IMO-8400 has been generally well tolerated across all dose cohorts to date, with patient exposure ranging from 2-46 weeks in the Phase 1/2 and extension trials. The most common adverse events reported to date include transient flu-like symptoms and injection site reactions. One serious adverse event of worsening grade 3 arthritis, deemed possibly related to study drug, was reported in a patient with a pre-existing history of arthritis in the 2.4 mg/kg dose cohort. This patient discontinued study treatment. To date, no other patients have discontinued treatment due to treatment-related adverse events. Preliminary evidence of clinical activity for IMO-8400 has been observed in all dose cohorts. In June 2015, an independent Data Review Committee reviewed 4-week safety data from the highest dose cohort and agreed that 2.4 mg/kg was safe for further evaluation. Safety, pharmacokinetics and preliminary activity for all three dose cohorts will be presented. Conclusions: IMO-8400 is a mutation-targeted therapy in development for the treatment of patients with relapsed or refractory WM. In an ongoing Phase 1/2 clinical trial in WM, IMO-8400 has been generally well tolerated and has demonstrated preliminary evidence of clinical activity. Safety results support continued evaluation of IMO-8400 at 2.4 mg/kg/week in this patient population. Disclosures Thomas: Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Beck:Idera Pharmaceuticals: Research Funding. Nashat:Idera Pharmaceuticals: Research Funding. Ansell:Idera Pharmaceuticals: Research Funding. Eradat:Idera Pharmaceuticals: Research Funding. Libby:Idera Pharmaceuticals: Research Funding. Hajdenberg:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Heffner:Idera Pharmaceuticals: Research Funding. Hoffman:Idera Pharmaceuticals: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Simov:Idera Pharmaceuticals: Employment. Wyant:Idera Pharmaceuticals: Employment. Brevard:Idera Pharmaceuticals: Employment. O'Leary:Idera Pharmaceuticals: Employment. Agrawal:Idera Pharmaceuticals: Employment.

Phase 1 study of CPX-1, a fixed ratio formulation of irinotecan (IRI) and floxuridine (FLOX), in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2014-2014 ◽  
Author(s):  
G. Batist ◽  
K. Chi ◽  
W. Miller ◽  
S. Chia ◽  
F. Hasanbasic ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Fixed Ratio ◽  
Compression Fracture ◽  
Drug Combinations ◽  
Molar Ratio ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3

2014 Background: In vitro studies have shown that varying the ratio of individual agents in drug combinations can result in synergistic, additive or antagonistic activity against tumor cells. CPX-1 is a liposomal formulation of IRI and FLOX in a fixed 1:1 molar ratio which was selected as optimal in vitro and confirmed to be synergistic in vivo in preclinical tumor models. CPX-1 overcomes the dissimilar pharmacokinetics (PK) of the individual drugs, enables sustained maintenance of this ratio after IV administration, and was evaluated in a Phase I open-label, dose-escalation study. Methods: Starting dose was 30 U/m2 (1 Unit of CPX-1 contains 1 mg IRI + 0.36 mg FLOX) given on day 1 and 15 of each 28-day cycle. Dose escalation was by modified Fibonacci with 4 subjects/cohort. Eligibility included: ≥ 18 yo; advanced solid tumor; ECOG PS ≤ 2; adequate bone marrow/liver/renal function. PK analysis was done on day 1 and 15 of the first cycle. Results: 26 subjects (16M:10F), median age 54.5 y (21–72), all with prior therapy, enrolled in 6 cohorts with the 5th cohort expanded to 6 subjects. Diagnoses: 8 colorectal, 3 pancreatic, 3 ovarian, 2 breast, 2 gastric, 2 esophageal, 2 sarcomas, 1 renal cell, 1 prostate, 1 NSCLC and 1 sphenoid sinus. Response: 20 subjects evaluable: 2 confirmed PRs (NSCLC 8+ wks; Colon 13+ wks, in a patient with prior IRI exposure) and 13 with SD (8–24+wks). Safety: DLTs were observed at the 6th dose level: 4 subjects with DLTs: 3 diarrhea (one resulting in death due to dehydration/ARF) and one neutropenia. Other possibly related grade 3 and 4 events included one each of: grade 3 diarrhea, grade 3 vomiting, grade 3 neutropenia, grade 3 fatigue, grade 3 compression fracture and arthralgia and pulmonary embolism grade 4. PK: In all 14 subjects analyzed to date the 1:1 molar ratio of IRI to FLOX was maintained for 24 hours and metabolites 5-FU and SN-38 were present in the plasma. Conclusions: CPX-1 represents a new approach to developing drug combinations in which drug ratios are pre-selected in vitro based on optimal antitumor activity and maintained systemically through pharmacokinetic control. Phase 2 studies are planned with a recommended dose of 210U/m2 of CPX-1. [Table: see text]

Pharmacokinetics and safety of an oral ALK inhibitor, ASP3026, observed in a phase I dose escalation trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2602-2602 ◽  
Author(s):  
Amita Patnaik ◽  
Patricia LoRusso ◽  
Howard A. Ball ◽  
Erkut Bahceci ◽  
Geoffrey Yuen ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Expansion Phase ◽  
Advanced Malignancies ◽  
Grade 3 ◽  
Ecog Ps ◽  
Clinical Trial Information

2602 Background: ASP3026 (3026) is a selective, potent, ATP-competitive, small molecule oral inhibitor of ALK receptor tyrosine kinase that has not previously been tested in humans. A Phase 1 dose-escalation trial, using a 3+3 design, evaluating 3026 as an oral single agent was conducted to investigate PK (Day 1 and Day 28), safety and clinical activity in patients (pts) with advanced malignancies (excluding leukemias) of ECOG PS 2 or less. Methods: 3026 was administered under fasting conditions on a continuous schedule to pts in successive dose-escalating cohorts at doses ranging from 25 mg QD to 800 mg QD. Results: Thirty pts were enrolled into the dose escalation part of the study. The MTD was determined based on DLT data from cycle 1. Three DLTs were observed: grade 2 nausea and vomiting leading to dose reduction at 525 mg QD; grade 3 rash leading to dose reduction, and grade 3 ALT/AST increase leading to study withdrawal at 800 mg QD. The most common AEs were constipation, vomiting, diarrhea, nausea and abdominal pain, and all AEs were manageable and reversible. Median AUC and Cmax increased proportionally with dose from 25 mg QD to 800 mg QD. There was no evidence of non-linear PK at ASP3026 doses >25 mg QD. The median terminal half-life was approximately 10 - 41 hours. Overall, A3026 appears well absorbed with median Tmax around 3 hours for both Day 1 and Day 28. Terminal T1/2 appears adequate for one daily dosing with median values ranging from approximately 18 to 34 hours. Based on visual inspection of pre-dose (trough) values from Days 8, 15, 22, and 28 it appears that steady-state conditions are achieved by day 28. Conclusions: The MTD of 3026 is 525 mg QD. Treatment with 3026 resulted in a promising safety and PK profile in pts with advanced malignancies. Further evaluation of 3026 in pts with tumors harboring gene mutation or ALK fusion genes in the cohort expansion phase at the MTD is ongoing. Clinical trial information: NCT01401504.

A phase I study of birinapant (TL32711) combined with multiple chemotherapies evaluating tolerability and clinical activity for solid tumor patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2504-2504 ◽  
Author(s):  
Ravi K. Amaravadi ◽  
Neil N. Senzer ◽  
Lainie P. Martin ◽  
Russell J. Schilder ◽  
Patricia LoRusso ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Clinical Benefit ◽  
Clinical Studies ◽  
Drug Exposure ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Drug Shortage ◽  
Apoptotic Pathway ◽  
Best Response

2504 Background: Birinapant (B) is a SMAC-mimetic that inhibits IAPs with excellent tolerability, drug exposure, target suppression and apoptotic pathway activation in clinical studies. Preclinical studies demonstrate potent anti-tumor synergy when B is combined with TNFa-inducing chemotherapies (CT). Methods: Escalating doses of B were combined with CT in a 5-arm 3+3 phase 1 study for adults (pts) with relapsed/refractory solid tumors to determine maximum tolerated dose (MTD), pharmacokinetics (PK), and efficacy to identify indications for further studies. The arms included carboplatin/paclitaxel (CP), irinotecan (I), docetaxel (D), gemcitabine (G), and liposomal doxorubicin (LD). Results: 124 pts were treated with B at doses of 2.8 to 47 mg/m2. The MTD of B for each arm was CP (47 mg/m2); I (22 mg/m2); D (47 mg/m2). The proposed G regimen could not be administered in heavily pretreated pts and B could not be evaluated for dose escalation; this arm was discontinued and no dose-limiting toxicities (DLT) occurred. LD drug shortage prevented dose escalation for B > 35mg/m2 (MTD not reached). B did not limit CT administration for CP, I, D, LD, supporting tolerable combination of B with CT. B-associated toxicity of Bell’s palsy (Grade 2) was considered a DLT and noted at higher dose levels for I, D, and LD, but not CP. This unusual reversible toxicity occurred during cycle 1 in 7 pts. Six of these pts continued therapy without recurrence. PK studies demonstrated no effect of B on CT. Except for CP, CT did not change the PK of B. CP increased plasma PK for B, possibly due to OATP1B3 transporter effects, but without increased B toxicities. 11 pts had a partial response, 61 pts had stable disease (>2 cycles, median 4.6 mo) and 37 pts had progressive disease as their best response, with clinical benefit (CR+PR+SD) of 58%. Conclusions: B can be combined with excellent tolerability with multiple CT at standard dosing. B plus CT demonstrated clinical benefit in many tumor types. Notable clinical activity occurred with I + B in pts who had failed prior I. These results support planning for further clinical studies of the I + B, and support the hypothesis for TNFa-mediated I + B synergy. Clinical trial information: NCT01188499.

Sign in / Sign up

Export Citation Format

Share Document