First-in-human phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of oral GNS561, a palmitoyl-protein thioesterase 1 (PPT1) inhibitor, in patients with primary and secondary liver malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16175-e16175
Author(s):  
James J. Harding ◽  
Ahmad Awada ◽  
Thomas Decaens ◽  
Gael Roth ◽  
Philippe Merle ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Oral Intake ◽  
Preliminary Evaluation ◽  
Minor Response ◽  
Activity Restriction ◽  
Liver Cancers ◽  
Palmitoyl Protein Thioesterase

e16175 Background: GNS561 belongs to a novel generation of drug blocking cancer cell proliferation by inhibiting late-stage autophagy and dose-dependent accumulation of enlarged lysosomes by interacting with palmitoyl-protein thioesterase-1 (PPT1). Methods: This phase I, multicenter, open-label, dose-escalation trial (3+3 design) explored two dosing schedules: one single oral intake three times a week and twice daily (BID) continuous oral intake of GNS561 in patients with advanced primary and secondary liver cancers (NCT03316222). The primary objective was to determine recommended phase II dose (RP2D) and schedule for further clinical development. The secondary objectives included a preliminary evaluation of the safety, pharmacokinetic (PK), pharmacodynamics (PD), and antitumor activity of GNS561. Results: Nineteen treatment-refractory patients were enrolled and were evaluable for primary endpoint: intrahepatic cholangiocarcinoma (iCCA) (9), hepatocellular carcinoma (HCC) (7), pancreatic ductal adenocarcinoma (PDAC) (2) and colorectal cancer (CRC) (1). Median age was 60, 89% were male and 37% had received 3 or more lines as prior cancer therapies. Dose escalation ranged from 50 mg three times a week to 200 mg BID. No dose-limiting toxicity were observed. Treatment-related adverse events were grade 1-2 gastrointestinal toxicity, primarily nausea/vomiting, occurring in 8 patients (42%) and diarrhea in 4 patients (21%). Occurrence of nausea/vomiting despite antiemetic prophylaxis prevented increasing doses above 200 mg BID. GNS561 displayed favorable bioavailability with interpatient variability (CV%: 13 to 223% and 21 to 98.2% on plasma concentrations on cycle 1 day 1 and cycle 2 day 1 respectively), and dose proportional exposure in plasma. GNS561 concentrations accumulated after multiple administration (2.60 - 9.00-fold) and exhibited a long half-life. Plasma and liver concentrations at doses ranging 100-200 mg BID were comparable to therapeutic exposures in preclinical models. Five patients (3 HCC and 2 iCCA) experienced tumor stabilization according to RECIST 1.1 criteria, including a minor response (-23%). Conclusions: GNS561 RP2D single agent was set at 200 mg BID based on this favorable safety profile and plasma exposure, GNS561 will be next further evaluated in monotherapy and in combination with checkpoint inhibitors considering the autophagic activity restriction of major histocompatibility complex-1 promotion of immune invasion. Clinical trial information: NCT03316222.

Phase I to II Multicenter Study of Oblimersen Sodium, a Bcl-2 Antisense Oligonucleotide, in Patients With Advanced Chronic Lymphocytic Leukemia

2005 ◽  
Vol 23 (30) ◽  
pp. 7697-7702 ◽  
Author(s):  
Susan M. O'Brien ◽  
Charles C. Cunningham ◽  
Anatoliy K. Golenkov ◽  
Anna G. Turkina ◽  
Steven C. Novick ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Phase Ii ◽  
Intravenous Infusion ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Lymphocytic Leukemia ◽  
Complete Disappearance ◽  
Continuous Intravenous Infusion

Purpose To determine the maximum-tolerated dose (MTD), efficacy, safety, and pharmacokinetics of oblimersen sodium in patients with advanced chronic lymphocytic leukemia (CLL). Patients and Methods Eligible patients had relapsed or refractory CLL after treatment with fludarabine. Oblimersen was administered at doses ranging from 3 to 7 mg/kg/d as a 5-day continuous intravenous infusion in cycle 1 and as a 7-day continuous intravenous infusion in subsequent cycles every 3 weeks in stable or responding patients. Results Forty patients were enrolled and treated (14 patients in phase I and 26 patients in phase II). Dose-limiting reactions in phase I included hypotension and fever, and the MTD for phase II dosing was established at 3 mg/kg/d. Two (8%) of 26 assessable patients achieved a partial response. Other evidence of antitumor activity included ≥ 50% reduction in splenomegaly (seven of 17 patients; 41%), complete disappearance of hepatomegaly (two of seven patients; 29%), ≥ 50% reduction of lymphadenopathy (seven of 22 patients; 32%), and ≥ 50% reduction in circulating lymphocyte counts (11 of 22 patients; 50%). Adverse events included transient hypotension, fever, fatigue, night sweats, diarrhea, nausea, vomiting, hypokalemia, and cough. Plasma concentrations of oblimersen (parent drug) and its major metabolites were variable. Renal clearance represented only a small portion of total parent drug clearance. Conclusion Dosing with oblimersen sodium in patients with CLL is limited by development of a cytokine release syndrome that is characterized by fever, hypotension, and back pain. Oblimersen sodium has modest single-agent activity in heavily pretreated patients with advanced CLL, and further evaluation of its activity in combination with cytotoxic drugs is warranted.

scholarly journals Quantitative PK/PD Prediction of the Efficacious and Safe Dose Ranges of the LMP7 Inhibitor M3258 for Phase I Application in Relapsed/Refractory Multiple Myeloma Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5582-5582
Author(s):  
Florian Lignet ◽  
Christina Esdar ◽  
Manja Friese-Hamim ◽  
Andreas Becker ◽  
Elise Drouin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research And Development ◽  
Phase I ◽  
Dose Escalation ◽  
Single Agent ◽  
Proteasome Inhibitors ◽  
Refractory Multiple Myeloma ◽  
Oral Application ◽  
Development Institute ◽  
Safe Dose

M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, β5i, PSMB8) proteolytic subunit of the immunoproteasome; a crucial component of the cellular protein degradation machinery, which is highly expressed in malignant hematopoietic cells including multiple myeloma. M3258 was previously shown to deliver strong in vivo preclinical efficacy in multiple myeloma xenograft models, as well as a more benign non-clinical safety profile compared to approved pan-proteasome inhibitors, exemplified by a lack of effects on the central and peripheral nervous systems and cardiac and respiratory organs. Here we describe preclinical PK/PD and PK/efficacy modelling which led to a prediction of the PK profile, and the efficacious and safe dose ranges of M3258 in human which were used to guide the design of the phase I dose-escalation trial of M3258 in >3 line relapsed/refractory multiple myeloma (RRMM) patients. Mouse, rat, dog and monkey PK, plasma protein binding and intrinsic clearance data were used to estimate a half-life of approximately 6 hours for M3258 in human. The human total clearance and volume of distribution for M3258 were predicted to be 0.033 L/h/kg and 0.28 L/kg, respectively, whilst oral bioavailability was estimated to be above 80%. LMP7 proteolytic activity was assessed as a PD readout in human multiple myeloma tumor cells xenografted to mice as well as in dog peripheral blood mononuclear cells (PBMCs). A strong PK/PD relationship was observed for M3258 across both species. LMP7 inhibition by M3258 also correlated strongly with anti-tumor efficacy in multiple myeloma xenografts, with maximal efficacy observed at M3258 exposure delivering sustained inhibition of tumor LMP7 activity. Quantitative PK/PD/efficacy modeling predicted the biologically efficacious dose (BED) of M3258 upon oral application to be between 10 - 90 mg daily in human. By incorporating data from nonclinical safety studies, these data suggest an attractive human PK profile of M3258, enabling oral application, as well as an improved human therapeutic index compared to approved pan-proteasome inhibitors. M3258 is being investigated in a phase I, first-in-man, 2-part, open label clinical study designed to determine the safety, tolerability, PK, PD and early signs of efficacy of M3258 as a single agent (dose-escalation) and co-administered with dexamethasone (dose-expansion) in participants with RRMM whose disease has progressed following > 3 prior lines of therapy and for whom no effective standard therapy exists. Integration of these data will guide the selection of the BED for potential further clinical development of M3258. Disclosures Lignet: Merck Healthcare KGaA: Employment. Esdar:Merck Healthcare KGaA: Employment. Friese-Hamim:Merck Healthcare KGaA: Employment. Becker:Merck Healthcare KGaA: Employment, Other: Holding shares with a value below 1000-USD. Drouin:EMD Serono Research and Development Institute: Employment. El Bawab:Merck Healthcare KGaA: Employment. Goodstal:EMD Serono Research and Development Institute: Employment. Gimmi:Merck Healthcare KGaA: Employment. Haselmayer:Merck Healthcare KGaA: Employment. Jährling:Merck Healthcare KGaA: Employment. Sanderson:Merck Healthcare KGaA: Employment. Sloot:Merck Healthcare KGaA: Employment. Stinchi:Merck Healthcare KGaA: Employment. Victor:Merck Healthcare KGaA: Employment. Walter:Merck Healthcare KGaA: Employment. Rohdich:Merck Healthcare KGaA: Employment.

Sequences of topotecan and cisplatin: phase I, pharmacologic, and in vitro studies to examine sequence dependence.

1996 ◽  
Vol 14 (12) ◽  
pp. 3074-3084 ◽  
Author(s):  
E K Rowinsky ◽  
S H Kaufmann ◽  
S D Baker ◽  
L B Grochow ◽  
T L Chen ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
In Vitro Studies ◽  
Pharmacokinetic Studies ◽  
Sequence Dependence ◽  
Renal Tubular

PURPOSE A phase I and pharmacologic study was performed to evaluate the feasibility of administering the topoisomerase I (topo I) inhibitor topotecan (TPT) in combination with cisplatin (CDDP) in minimally pretreated adults with solid tumors. The study was designed to evaluate the magnitude of the toxicologic and pharmacologic differences between the two sequences of drug administration. MATERIALS AND METHODS TPT was administered as a 30-minute infusion daily for 5 days and CDDP was given either before TPT on day 1 or after TPT on day 5. Each patient was treated with both schedules on an alternating basis every 3 weeks. Sequential dose escalation of TPT or CDDP resulted in three dosage permutation of TPT/CDDP (mg/m2): 0.75/50, 1/50, and 0.75/75. After the maximum-tolerated dose (MTD) level was achieved, the feasibility of using granulocyte colony-stimulating factor (G-CSF) to permit further dose escalation was studied. To examine the interaction of TPT and CDDP in vitro, human A549 lung cancer cells were exposed to these agents concurrently and sequentially. RESULTS Dose-limiting neutropenia and thrombocytopenia resulted after the doses of TPT or CDDP were increased to greater than 0.75 and 50 mg/m2, respectively, without and with G-CSF. The sequence of CDDP before TPT induced significantly worse neutropenia and thrombocytopenia than the alternate sequence. In vitro studies failed to provide any evidence for the differences in the cytotoxicity of these two sequences. Instead, pharmacokinetic studies suggested that the differences in toxicity were due, in part, to lower TPT clearance and exposure when CDDP preceeds TPT, possibly due to subclinical renal tubular toxicity induced by CDDP. CONCLUSION The sequence of CDDP before TPT at doses of 50 and 0.75 mg/m2, respectively, is recommended for subsequent clinical trials in tumor types in which both agents have significant single-agent activity. The potential for sequence-dependent cytotoxic, toxicologic, and pharmacologic effects should be evaluated in concurrent clinical and laboratory studies in the course of developing combination chemotherapy regimens that consist of topo I-targeting agents and other antineoplastic agents, particularly DNA-damaging agents.

Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors.

1997 ◽  
Vol 15 (2) ◽  
pp. 773-780 ◽  
Author(s):  
C A Johnson ◽  
D Kilpatrick ◽  
R von Roemeling ◽  
C Langer ◽  
M A Graham ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Performance Status ◽  
Single Agent ◽  
Maximum Plasma ◽  
Time Curve ◽  
Minor Response ◽  
Heavily Pretreated ◽  
Previously Treated ◽  
A Minor

PURPOSE AND METHODS Tirapazamine (SR4233, WIN 59075) is a benzotriazine-di-N-oxide bioreductive agent that is selectively activated to a reactive DNA-damaging species in hypoxic tumors. Preclinical studies show that synergistic antitumor activity results from a schedule-dependent interaction between tirapazamine and several cytotoxic drug classes, including cisplatin. In a phase I combination study, tirapazamine (130 to 260 mg/m2) was administered as a 1-hour intravenous (IV) infusion beginning 3 hours before cisplatin (75 to 100 mg/m2). Thirteen patients received 41 courses of therapy. These patients had an excellent performance status and were not heavily pretreated. The predominant diagnosis was lung cancer. RESULTS The major acute side effects were nausea and vomiting, which were controlled with an intensive antiemetic regimen. Other acute effects included diarrhea and muscle cramping, while with repeated dosing, anorexia and fatigue predominated. Full doses of each agent were well tolerated in combination, although in this previously treated population, fatigue increased markedly after three cycles of therapy. Partial responses were observed in two patients (one with non-small-cell lung cancer and one with breast cancer), and a minor response occurred in a patient with mesothelioma. Tirapazamine pharmacokinetics were linear with respect to increasing dose with a mean maximum plasma concentration (Cmax) of 5.97 +/- 2.25 microg/mL and an area under the concentration-time curve (AUC) of 811.4 +/- 311.9 microg/mL.min at 260 mg/m2. These results are consistent with other ongoing single-agent and combination studies and indicate that therapeutically relevant levels of tirapazamine are achievable in patients based on animal models. The mean cisplatin AUC was 285.6 +/- 46.4 microg/mL.min with mean Cmax values of 3.38 +/- 0.43 microg/mL at 75 mg/m2. The clearance of cisplatin was unaffected by coadministration with tirapazamine. CONCLUSION This trial shows that in previously treated patients, full doses of cisplatin are well tolerated with increasing doses of tirapazamine up to 260 mg/m2. The observation of clinical responses in this trial supports the phase II investigation of this regimen.

Results of a Phase I Trial of SGN-40 (Anti-huCD40 mAb) in Patients with Relapsed Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3576-3576 ◽  
Author(s):  
Mohamad A. Hussein ◽  
James R. Berenson ◽  
Ruben Niesvizky ◽  
Nikhil C. Munshi ◽  
Jeffrey Matous ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Aseptic Meningitis ◽  
Dose Escalation ◽  
Single Agent ◽  
Objective Response ◽  
Lymphocytic Leukemia ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Grade 3

Abstract SGN-40 is a humanized anti-CD40 monoclonal antibody that has demonstrated potent in vitro and in vivo efficacy against cell lines expressing CD40, a member of the tumor necrosis factor receptor family. CD40 is widely expressed on tumors of B-cell origin, including myeloma, non-Hodgkin’s lymphoma, Hodgkin’s disease, and chronic lymphocytic leukemia. SGN-40 has been evaluated in a phase I, multi-dose, single-agent, dose escalation study for patients with relapsed or refractory multiple myeloma. This single-arm trial was designed to evaluate safety, pharmacokinetics, immunogenicity, and antitumor activity. Thirty-two patients were treated at five clinical sites. Patients had been heavily pretreated with a median of four prior regimens and 4.8 years since diagnosis. Initially, patients were treated with four weekly infusions at a cohort-specific dose. This schedule was well-tolerated at 0.5, 1.0 and 2.0 mg/kg/wk; however, two of three patients experienced dose-limiting toxicities following the first dose at 4 mg/kg. One patient had aseptic meningitis (grade 3) and another had headache (grade 3) and aseptic meningitis (grade 4); both patients fully recovered after several days of symptom management. Subsequently, the protocol was amended to allow intra-patient dose-loading, which resulted in successful dose escalation to 8 mg/kg, the highest dose tested. There was neither recurrence of grade 3 neurotoxicity nor evidence of cumulative toxicity. Drug-related adverse events were mostly grade 1 or 2 and included: fatigue (38%), headache (34%), nausea (16%), conjunctivitis (13%), diarrhea (13%), vomiting (13%), anemia (9%), anorexia (9%), chills (9%), and pyrexia (9%). Transient grade 3 elevation of hepatic transaminases (1) and grade 3 neutropenia (1) were observed. Overall, toxicity did not appear to increase in incidence or severity at higher doses. Patients were evaluated at baseline and end of treatment for development of anti-SGN-40 antibodies. Of 30 patients for whom appropriate samples were available for testing, only one low-titer immune response (16 ng/mL) was detected, suggesting that immunogenicity does not appear to be a significant problem in this patient population. Pharmacokinetic analysis demonstrates dose-proportional changes in Cmax and AUC with a relatively short terminal half-life, similar to that seen in non-human primates. Final analysis of SGN-40 serum levels is ongoing. Although several patients demonstrated decreased M-protein and improvement in subjective symptoms, no patients met criteria for objective response. Five patients (16%) had stable disease at the time of restaging. In summary, dose-dependent toxicity was established only in relation to the first dose of SGN-40, which may be due to partial agonistic signal transduction. Using a dose-loading schedule, SGN-40 was administered up to 8 mg/kg without reaching a maximum tolerated dose. Some patients with advanced myeloma appeared to derive clinical benefit from therapy, and further development of this antibody, either as monotherapy or in combination with other anti-myeloma therapies, is indicated.

Phase I, Dose-Escalation Study of 2 Dosing Regimens of AS703569, An Inhibitor of Aurora and Other Kinases, Administered Orally in Patients with Advanced Hematological Malignancies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2963-2963 ◽  
Author(s):  
Anne Sonet ◽  
Carlos Graux ◽  
Johan Maertens ◽  
Christine-Maria Hartog ◽  
Justus Duyster ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Preliminary Data ◽  
Hematological Malignancies ◽  
Single Agent ◽  
Gi Bleeding ◽  
Dose Escalation Study ◽  
Inhibition Of Proliferation ◽  
Dosing Regimens ◽  
Grade 3

Abstract Background: AS703569 is a novel, orally bioavailable, potent ATP-competitive, small molecule that inhibits all three aurora kinase isoforms (A, B, and C), and shows inhibitory activity across other kinases involved in cell proliferation and survival, including FLT3, ABL1, ABL1 (mut. T315I), JAK-2, and FGFR3. AS703569 has been tested as a single agent and in combination with standard-of-care anticancer agents in leukemia cell lines, freshly isolated leukemic cells, and tumor xenograft models. The strong inhibition of proliferation and the triggering of apoptosis induced by AS703569 lead to significant anti tumor activity resulting in tumor regression or growth delay, and prolongation of animal survival. AS703569 is currently being tested in phase I studies as a single agent and in combination; the main objectives are to establish the MTD (based on dose-limiting toxicities [DLTs]) and evaluate the safety and PK/PD effects of different regimens. Study design: This is an open-label, phase I, two-arm, dose-escalation study in patients (pts) with AML, CML, MDS, and MPD. Patients were sequentially assigned to one of two AS703569 dosing regimens: Regimen 1: once daily (QD), days 1–3 and 8–10 of a 21-day cycle; Regimen 2: QD, days 1–6 of a 21-day cycle. In both treatment arms, AS703569 was administered at escalating dose levels (DL; 3, 6, 10, 15, 21, 28, and 47 mg/m2/day) using a 3+3 cohort design. Repeated cycles were permitted until disease progression or unacceptable toxicity. Patient characteristics: Pt characteristics are summarized in the Table. Pts had primary AML (n=20), secondary AML (n=13), CML (n=6), MDS (n=5), and MPD (n=1). Pts were heavily pretreated and had failed previous chemotherapy. Safety: The median number of AS703569 cycles received per pt was 2 for Regimen 1 (range 1–7) and 1 for Regimen 2 (range 1–6). In Regimen 1, at DL 7 (47 mg/m2/day, n=3), 2 subjects reported DLTs: 1 case of grade 3 diarrhea with hyponatremia and sepsis with a fatal outcome, and 1 case of grade 3 diarrhea with GI bleeding. In Regimen 2, at DL 7 (n=5), 3 subjects reported DLTs: 2 cases of grade 4 mucositis and 1 case of neutropenic infection. Consequently, the dose was de-escalated to 37 mg/m2/day for both regimens and enrollment is ongoing at this DL to confirm the MTD. Grade ≥3 toxicities reported throughout the study mainly included infections (18 pts), neutropenia and febrile neutropenia (17 pts), thrombocytopenia (15 pts), anemia (11 pts), and GI disorders including mucositis, diarrhea and GI bleeding (8 pts). Alopecia was reported in some pts. PK: Preliminary data for 37 pts (DL 1–6) show an increased exposure with dose, a Tmax of 2–4 h (range 0.5–8 h), and an effective half-life of ~10–20 h. Activity (preliminary data): In Regimen 1, 1 pt with refractory CML (mut. T315I) has received 7 treatment cycles and shown a hematological and cytogenetic response; 5 pts with AML received 5–7 cycles, 3 achieved reduction in BM and/or peripheral blasts. In Regimen 2, 1 pt with MDS received 6 cycles and achieved a PR; 2 pts with AML received 3 cycles and did not progress. Conclusions: These data indicate that AS703569, QD, days 1–3 and 8–10 every 21 days or on days 1–6 every 21 days is generally well tolerated in pts with advanced hematological malignancies. Most grade 3/4 toxicities are commonly seen in pts with advanced hematological malignancies and are in part linked to the underlying disease. A DL with an unacceptable frequency of DLTs was reached and enrollment continues at a lower DL to confirm the MTD. Early evidence of activity was observed in pts with CML, AML, and MDS. Regimen 1 Regimen 2 N 24 21 Median (range) age, years 69.5 (48–83) 71 (49–82) Sex, M/F 15/9 12/9 ECOG PS, 0-1-2 5-12-7 3-12-6 Median (range) previous lines of therapy 3 (1–6) 2 (1–6)

Phase I Study of Lenalidomide in Acute Leukemia: Remissions in Post-Allogeneic Relapse of Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 841-841 ◽  
Author(s):  
Jason C. Chandler ◽  
Rebecca B. Klisovic ◽  
Mitch A. Phelps ◽  
Alison Walker ◽  
Ramiro Garzon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Leukemia ◽  
Phase I ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Allogeneic Transplantation ◽  
Initial Therapy ◽  
Trisomy 13 ◽  
Acute Myeloid

Abstract Abstract 841 Lenalidomide is effective in myeloma and low-risk myelodysplastic syndromes (MDS), especially MDS with the 5q- cytogenetic abnormality, and may also have activity in acute leukemia. We designed a phase I dose escalation trial of lenalidomide in adults with relapsed or refractory acute leukemia to determine the maximum tolerable dose (MTD) and dose limiting toxicity (DLT), as well as to provide preliminary efficacy data in this setting. 35 adults with acute leukemia were enrolled: 31 with acute myeloid leukemia (AML) and 4 with acute lymphoblastic leukemia (ALL). Patients had a median age of 63 years (range, 22-79) and had received a median of 2 prior therapies (range, 1-4). 8 patients had relapsed after transplantation (7-allogeneic, 1-autologous). Patients were treated orally with lenalidomide on days 1-21 of 28 day cycles at the following dose levels: 25mg/day (N=4), 35mg/day (N=9), 50mg/day (N=19, including the expansion at the MTD), and 75mg/day (N=3). Patients were eligible to receive additional cycles of treatment beyond cycle 1 in the absence of disease progression defined as 25% increase in blasts relative to pretreatment. The median number of cycles received was 1 (range, 1-7). DLTs were assessed during cycle 1 of therapy. DLTs were sudden death (N=1, autopsy ruled out pulmonary embolism), rash (N=1), line-associated thrombosis (N=1), and fatigue (N=3). Grade 3 fatigue occurred in two patients at 75mg/day; 50mg/day was thus declared the recommended phase 2 dose and 10 additional patients were treated at this dose. The major toxicities associated with treatment were drug and disease associated myelosuppression and infection, as expected; these did not constitute DLT. In spite of concerns that higher dose lenalidomide would be associated with increased risk of thromboembolism, this toxicity was infrequent, even during multiple cycles of therapy. Two events occurred; both were line associated, and neither was life-threatening. Detailed pharmacokinetic results for the dose escalation cohorts in the trial are listed in the table below. Maximum plasma lenalidomide concentrations and area under the concentration-time curve (AUC) increased proportionally with dose. Drug clearance was independent of dose and correlated with calculated creatinine clearance. Of 31 patients with AML there were 5 complete responses (CR) (by IWG criteria for AML; Cheson, JCO 2003). 3/3 with cytogenetically abnormal AML achieved cytogenetic CR (cCR) as well. Achievement of CR was delayed beyond 2 months from initiation of therapy in each case. The duration of CR was 2.4-8.8 months, with two responders still in CR at 2.4+ and 4.7+ months, respectively. At 25mg, a 74 year old with AML in 2nd relapse with widespread leukemia cutis but no blood/marrow involvement had resolution of disease after 2 cycles. At 35mg, a 69 year old with AML and trisomy 13 achieved cCR after 2 cycles. At 50mg, there were three CRs, including two patients who received lenalidomide as initial therapy for relapsed AML following allogeneic stem cell transplant. In both of these cases, lenalidomide therapy was associated with the onset of skin rash requiring temporary discontinuation of drug; CR was achieved after 2 to 3 cycles of therapy and was preceded by cytogenetic remission before count recovery occurred. A third CR at the 50mg level occurred in a 70 year old with AML who had lenalidomide discontinued after 2 cycles due to no apparent response. Subsequently, CR was achieved 1 month later with no intervening therapy. In conclusion, single agent lenalidomide induced CR in 16% (5/31) of relapsed/ refractory AML patients. None of the responders had 5q-. The DLT was fatigue; the MTD was 50mg daily for days 1-21. Achievement of CR without donor leucocyte infusion in 2/4 patients who received lenalidomide as initial therapy for AML relapse following allogeneic transplantation suggests a possible allogeneic immunomodulatory effect. We are now developing a CTEP-sponsored study of lenalidomide as maintenance following allogeneic transplantation for AML. The promising single agent efficacy reported here supports further study of lenalidomide in combination with other agents in high risk AML. Disclosures: Blum: Celgene: Research Funding.

SAR650984, a CD38 Monoclonal Antibody In Patients With Selected CD38+ Hematological Malignancies- Data From a Dose-Escalation Phase I Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 284-284 ◽  
Author(s):  
Thomas G Martin ◽  
Stephen A. Strickland ◽  
Martha Glenn ◽  
Wei Zheng ◽  
Nikki Daskalakis ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Adverse Events ◽  
Phase I ◽  
Median Time ◽  
Dose Escalation ◽  
Standard Therapy ◽  
Hematological Malignancies ◽  
Dose Range ◽  
Single Agent ◽  
Heavily Pretreated

Abstract Background SAR650984 (SAR) is a naked humanized IgG1 monoclonal antibody (mAb) that binds selectively to the human surface antigen CD38 highly expressed in multiple myeloma cells and other hematological malignancies. SAR kills tumor cells via 3 different biological mechanisms: Antibody-dependent cellular-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and Induction of apoptosis (pro-apoptosis). Here we present preliminary data from the ongoing first in human, Phase I dose escalation study of SAR in patients with selected CD38+ hematological malignancies. (clinicaltrials.gov: NCT01084252) Objectives The primary objective is to determine the maximum tolerated dose (MTD). Secondary objectives include characterization of safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity and disease response. Methods SAR is administered as a single agent IV infusion every week (QW) or every 2 weeks (Q2W) to adult patients with selected CD38+ hematological malignancies who have progressed on or after standard therapy or for whom no effective standard therapy exists. An accelerated dose escalation schedule was used for the first 5 dose levels (DL) (0.0001 mg/kg to 0.1 mg/kg Q2W), with one evaluable patient per DL unless DLT was experienced. All subsequent DL (0.3 mg/kg, 1 mg/kg, 3 mg/kg, 5mg/kg, 10 mg/kg, 20 mg/kg Q2W and 10 mg/kg QW), followed the classic 3+3 design for dose escalation based on DLT. Results 32 patients have been treated across all DLs including 3 patients with NHL, 2 with CLL, and 27 with MM. The 20 mg/kg Q2W and 10 mg/kg QW DLs are currently being evaluated and the MTD has not been reached. DLTs have been limited to Grade (G) 2 infusion reactions during cycle 1 with 1 at DL 0.3 mg/kg and 1 at DL 3.0 mg/kg. This was mitigated by the implementation of routine pretreatment with methylprednisone, diphenhydramine, ranitidine and acetaminophen. The most frequent occurring adverse events (≥ 10%) all DL, regardless of causality, are fatigue (46.9%), nausea (31.3%), pyrexia (28.1%), cough (25%), vomiting (21.9%), hypercalcemia (18.8%), with headache, constipation, bone pain, chills and diarrhea each occurring in 15.6% of patients. In addition, pneumonia, anemia, dysgeusia and hypokalemia each occurred in 12.5% of patients. Serious adverse events considered related to therapy include G 3 pneumonia (6.3%) associated with fever (3.1%), hyperglycemia (3.1%) and one Grade 2 infusion reaction (3.1%). Of the 19 patients treated at DL 1.0 mg/kg to 10 mg/kg Q2W, 1 had CLL, 1 had NHL and 17 had MM. The 17 MM patients were older and heavily pretreated patients; median age of 64 years (range: 55-74); and median of seven prior regimens (range: 2-14). All MM patients had received prior lenalidomide and bortezomib. The median time from diagnosis to first SAR650984 dosing was 6. 8 years (range 1.8 – 16.8 years). Responses in this group (fig 1), according to EBMT MM criteria, included 1 PR at 1 mg/kg (n = 3) and 5 mg/kg (n=3), and 1 MR at DL 3 mg/kg (n = 6). The 10 mg/kg DL demonstrated 3 PR and 2 SD among 6 MM patients treated. For the 19 patients treated at or above the 1 mg/kg DL the median time on treatment is 8 weeks (range 2-50 weeks). Immunogenicity studies show no anti-SAR antibodies. Receptor Occupancy could be detected from DL 1 mg/kg and reached a range of 84.1 to 97.7 % at 10 mg/kg. PK analysis show a more than dose proportional increase of exposure over the 0.03 to 10 mg/kg dose range with clearance in a similar range between 5 mg/kg and 10 mg/kg. No accumulation was observed based on Cmax at cycle 2 over the 0.03 to 3 mg/kg dose range. Tumor growth inhibition threshold was reached at Cmax for 1 patient at DL 5 mg/kg and 5 patients at DL 10 mg/kg. Conclusion The safety profile of SAR is predictable and manageable and the MTD has not been reached. SAR demonstrates encouraging single agent activity in patients with heavily pretreated RRMM and warrants further evaluation in this patient population. Disclosures: Zheng: sanofi: Employment. Daskalakis:sanofi: Employment.

Phase I study of vorinostat, a histone deacetylase (HDAC) inhibitor, in combination with carboplatin (Cb) and paclitaxel (P) for patients with advanced solid malignancies (NCI #6922)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2077-2077 ◽  
Author(s):  
S. Ramalingam ◽  
R. A. Parise ◽  
M. J. Egorin ◽  
A. Argiris ◽  
R. Stoller ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Human Carcinoma ◽  
Carcinoma Cell Lines ◽  
Solid Malignancies ◽  
Human Carcinoma Cell ◽  
Oxobutanoic Acid ◽  
Recommended Phase Ii Dose

2077 Background: Vorinostat (SAHA) induces differentiation & growth arrest in a variety of human carcinoma cell lines by inhibiting HDAC. It also enhances the efficacy of chemotherapy. We are conducting a phase I study to evaluate the combination of vorinostat, Cb & P for patients with advanced solid malignancies. Methods: Patients with advanced solid malignancies who were candidates for combination therapy with Cb & P were eligible. Vorinostat was given orally on d 1–14 of each 21-d-cycle, except in cycle 1 when begun on d -4 to facilitate PK studies. Cb & P were given on d 1 of each cycle. Plasma concentrations of vorinostat, & its 2 major metabolites were quantitated with a novel LC-MS/MS assay. Results: Dose level 4 has been determined as the recommended phase II dose (RP2D) for the combination, since the RP2D of single agent vorinostat is 400 mg on this schedule. Observed toxicities included nausea, vomiting, neutropenia & thrombocytopenia, none of which were dose-limiting. Of 9 patients evaluable for response, 4 had PR (1 head & neck cancer, 3 non-small cell lung cancer), & 2 had stable disease. Vorinostat was rapidly absorbed & AUC increased with dose. Vorinostat PK parameters included Tmax 0.5–2 h, t1/2 1.6 ± 0.5 h, & CL/F 5.8 ± 1.7 l/min. Cb & P did not alter vorinostat PK. 4-Anilino-4-oxobutanoic acid was the major, & long-lived, vorinostat metabolite, with Cmax 1.5–7 fold > vorinostat Cmax & t ½ ∼6h. Vorinostat glucuronide Cmax was 1–5 fold > vorinostat Cmax & glucuronide t ½ ∼2h. The RP2D cohort is being expanded to 12 patients to obtain additional clinical & PK data. Conclusions: Vorinostat can be safely administered in combination with Cb & P at their recommended doses. Vorinostat PK are not altered by Cb & P. Promising anti-cancer activity has been noted in patients with advanced NSCLC. Support: U01CA099168–01, U01CA62505, NIH/NCCR/GCRC grant 5M01RR 00056. [Table: see text] No significant financial relationships to disclose.

A phase I study of BMS-582664 (brivanib alaninate), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in combination with full-dose cetuximab in patients (pts) with advanced gastrointestinal malignancies (AGM) who failed prior therapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14018-14018 ◽  
Author(s):  
C. R. Garrett ◽  
L. L. Siu ◽  
G. Giaccone ◽  
A. El-Khoueiry ◽  
J. Marshall ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Fdg Pet ◽  
Kinase Inhibitor ◽  
Imaging Modality ◽  
Single Agent ◽  
Dual Inhibitor ◽  
Gastrointestinal Malignancies ◽  
Full Dose ◽  
Prior Therapy

14018 Background: Brivanib is an oral prodrug of BMS-540215, a dual tyrosine kinase inhibitor of VEGFR and FGFR signaling. Prior studies have validated both VEGF and EGF signaling pathways as targets in AGM. The MTD of single-agent brivanib is 800 mg qd (ASCO #3051, 2006). Methods: An open-label Phase I dose-escalation study of brivanib in combination with cetuximab was conducted in pts with AGM who failed prior therapy. Brivanib was given po Day 1 and qd from Day 8, starting at 320 mg. Cetuximab was given IV Day 8 (400 mg/m2) then weekly (250 mg/m2). Dose escalation of brivanib continued to 800 mg qd, when an expansion cohort for pts with colorectal cancer (CRC) was opened for additional safety and efficacy. Fresh tissue and blood sampling for biomarker and pharmacokinetic (PK) analysis was performed. FDG-PET was obtained at Baseline X 2, Days 15 and 56. Tumor response (modified WHO) was evaluated q 8 weeks. Results: 18 pts (15 CRC, 2 esophageal, 1 other) were treated with 320, 600 or 800 mg qd of brivanib in combination with cetuximab for a median of 8 weeks (range 1 - 20+). A single DLT, bilateral pulmonary emboli, occurred at 320 mg qd. Few treatment-related AEs occurred across the 3 cohorts (Table). PK/biomarker data is pending. Available FDG-PET results from measurements in 8 pts with 2–3 target lesions showed good baseline reproducibility in SUVpeak, SUVmean and SUVmax, with intra-subject CV of 3.6%, 7.2% and 9.3%, respectively. Conclusions: Brivanib in combination with full-dose cetuximab was well tolerated at ≤800 mg qd and did not result in enhancement of cetuximab associated AEs. Pre-treatment FDG-PET is a highly reproducible imaging modality. [Table: see text] [Table: see text]

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