scholarly journals Phase I dose-escalation study of the safety, tolerability, and pharmacokinetics of aflibercept in combination with S-1 in Japanese patients with advanced solid malignancies

2020 ◽  
Vol 38 (5) ◽  
pp. 1390-1399
Author(s):  
Toshihiko Doi ◽  
Narikazu Boku ◽  
Yusuke Onozawa ◽  
Keishiro Takahashi ◽  
Osamu Kawaguchi ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Japanese Patients ◽  
Maximum Tolerated Dose ◽  
Reversible Posterior Leukoencephalopathy Syndrome ◽  
Pharmacokinetic Analysis ◽  
Dose Escalation Study ◽  
Posterior Leukoencephalopathy

SummaryBackground Aflibercept, a recombinant fusion protein binding VEGF-A, VEGF-B and placental growth factor, inhibits tumor growth by blocking angiogenesis. The aim of this phase I dose-escalation study was to determine the recommended phase II dose (RP2D) of aflibercept in combination with S-1 in Japanese patients with solid tumors. Patients and methods Sequential cohorts of 3–6 patients with metastatic or unresectable solid tumors, who had failed at least one prior line of standard treatment or who were not suitable for such treatment, were to receive escalating doses of aflibercept every 2 weeks, starting at 2 mg/kg, combined with S-1 at 40 mg/m2 twice daily (80 mg/m2/day; 4 weeks on/2 weeks off). Dose-escalation was to be based on the incidence of dose-limiting toxicity (DLT). Blood samples were collected for pharmacokinetic analysis. Results At the first dose level (aflibercept 2 mg/kg plus S-1) 1 of 6 patients experienced a DLT (grade 4 proteinuria). The aflibercept dose was consequently escalated to 4 mg/kg; 1 of 3 patients treated at this dose level had a DLT (grade 2 pleural effusion), and another patient experienced grade 3 reversible posterior leukoencephalopathy syndrome after the DLT assessment period. Additional patients were therefore enrolled into the first dose level to explore safety and tolerability. The study was subsequently terminated prematurely. The maximum tolerated dose was not reached and the RP2D was not determined in Japanese patients. Conclusions The tolerability and safety of aflibercept 2 mg/kg in combination with S-1 was confirmed in Japanese patients with advanced solid tumors.

Phase I study of ABT-751 in combination with CAPIRI (capecitabine and irinotecan) and bevacizumab in patients with advanced colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13553-13553
Author(s):  
W. A. Messersmith ◽  
M. A. Rudek ◽  
D. Laheru ◽  
M. Zhao ◽  
P. He ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Combination Therapy ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Advanced Colorectal Cancer ◽  
Standard Of Care ◽  
Maximum Tolerated Dose ◽  
Total Daily Dose ◽  
Dose Escalation Study

13553 Background: ABT-751 (A) is an orally (PO) bioavailable sulfonamide with antimitotic properties. We are performing a non-randomized phase I/II dose-escalation study of A in combination with capecitabine (C), irinotecan (I) and bevacizumab (B) to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) in patients with advanced colorectal cancer (1st or 2nd line). Methods: Patients are treated with A QD for 7d (lead-in) and then begin 21-d cycles of treatment with A (QD) and C (BID) d1–14 PO, I d1 IV, and B d1 IV. Dose escalation started at dose level (DL) 1 at A 150 mg, I 200 mg/m2, and C 1600 mg/m2 (total daily dose) and escalated to full dose CAPIRI (I 250 mg/m2, and C 2000 mg/m2) for DL2. B was then added as standard of care at 7.5 mg/kg for DL2b (and later, DL1b). Blood samples were collected for pharmacogenomics (PG), pharmacodynamics (PD), steady-state PK of A and A metabolites when administered alone or in combination with C, I, and B, and PK of I and I metabolites. Serial dynamic contrast MRI’s, before and after the ABT-751 monotherapy lead-in period, are being performed in a subset of subjects. Results: Eight patients have been treated at dose levels 1 (3), 2 (2), and 2b (3). One patient on DL2 experienced g3 transaminitis and another on DL2b had F&N which were dose-limiting. Dose level 1 is being expanded to 6 patients, now with B (DL1b). Other g3/4 toxicities have included g4 neutropenia (1 subject DL2, 1 DL2b). The formation of A glucuronide appears decreased during combination therapy (see table). I PK, PD, and PG samples were collected and analysis is pending. Of 8 subjects, there have been 4 PD and 4 SD after 2 cycles. Conclusions: The combination therapy of A 150 mg and 20% dose-reduced CAPIRI appears well-tolerated. Patient accrual continues at DL1b. [Table: see text] No significant financial relationships to disclose.

Phase I dose escalation study of the anti-IGF-1R monoclonal antibody CP-751,871 in patients with refractory solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3586-3586 ◽  
Author(s):  
P. Haluska ◽  
H. Shaw ◽  
G. N. Batzel ◽  
L. R. Molife ◽  
A. A. Adjei ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Receptor Internalization ◽  
Pharmacokinetic Analysis ◽  
Adrenocortical Cancer ◽  
Dose Escalation Study ◽  
Multiple Tumor ◽  
Grade 3

3586 Background: The insulin-like growth factor 1 receptor (IGF-IR), a tyrosine kinase, and its ligands (IGF-I & -2) are upregulated in many human tumors (e.g., breast, prostate, colon and non-small cell lung cancer) and enhance proliferative and prosurvival signaling. Inhibition of IGF-IR activation in tumor models suppresses tumor growth and increases tumor sensitivity to chemotherapy, supporting the development of agents targeting IGF-IR. CP-751,871 is a potent, highly specific, fully humanized, monoclonal antibody that inhibits IGF-IR autophosphorylation and induces receptor internalization. Methods: A Phase I dose escalation study was initiated to define the safety and tolerability, and to characterize the pharmacokinetic properties of CP-751,871 in patients with advanced solid tumors refractory to standard therapies. Results: Following informed consent and screening, a total of 24 patients with refractory solid tumors (e.g. colorectal, NSCLC, sarcoma and prostate cancer; 1–6 previous regimens) were enrolled. Patients received 3 to 20 mg/kg of CP-751,871 by IV infusion on Day 1 of 3-week cycles in four dose-escalation cohorts of 3 patients. No dose limiting toxicities were identified and the maximum feasible dose (MFD) cohort of 20 mg/kg was extended with 12 additional patients. No higher than grade 3 CTCAE v3.0 toxicities, attributed to study drug, have been so far reported. Grade 3 toxicities, all reported in patients dosed with 20 mg/kg of CP-751,871, are increased GGT (4%) and fatigue (4%). Grade 2 toxicities include: anorexia (7%), diarrhea (7%), increased GGT (4%), hyperglycemia (4%), fatigue (4%), increased urinary frequency (4%), nausea (4%), increased ALT (4%) and increased AST (4%). Pharmacokinetic analysis is currently ongoing. No objective responses were observed. At the MFD, patients received a median of 4 cycles (1–16). Three patients were stable for > 6 months and one patient, currently at cycle 16, remains on study. An additional cohort of 12 adrenocortical cancer patients is under evaluation. Conclusions: These data indicate that CP-751,871 is safe and well tolerated. Due to its good safety profile, CP-751,871 may constitute a suitable targeted agent to use in combination with approved therapies in multiple tumor types. No significant financial relationships to disclose.

scholarly journals Phase I dose‐escalation study of capmatinib ( INC 280) in Japanese patients with advanced solid tumors

2019 ◽  
Vol 110 (4) ◽  
pp. 1340-1351 ◽  
Author(s):  
Taito Esaki ◽  
Fumihiko Hirai ◽  
Akitaka Makiyama ◽  
Takashi Seto ◽  
Hideaki Bando ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Japanese Patients ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study

scholarly journals Phase I dose‐escalation study of buparlisib ( BKM 120), an oral pan‐class I PI 3K inhibitor, in Japanese patients with advanced solid tumors

2014 ◽  
Vol 105 (3) ◽  
pp. 347-353 ◽  
Author(s):  
Yuichi Ando ◽  
Megumi Inada‐Inoue ◽  
Ayako Mitsuma ◽  
Takayuki Yoshino ◽  
Atsushi Ohtsu ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Japanese Patients ◽  
Class I ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study

Phase I/II Study of Bortezomib in Combination with Liposomal Doxorubicin and Melphalan in Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5182-5182 ◽  
Author(s):  
Ajai Chari ◽  
Lawrence Kaplan ◽  
Charles Linker ◽  
Lloyd E. Damon ◽  
Willis H. Navarro ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Progressive Disease ◽  
Liposomal Doxorubicin ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Heavily Pretreated ◽  
Level 1 ◽  
Grade 3

Abstract Phase I/II studies using either liposomal doxorubicin (D) or oral melphalan (M) in combination with the proteasome inhibitor bortezomib (V) have found favorable efficacy and tolerance in patients with relapsed and refractory MM. Since these drugs have different mechanisms of action and toxicity profiles, we initiated a phase I/II study to examine the safety and efficacy of combining all three agents (DMV) in relapsed or refractory myeloma. Study Aims: Starting at 25–50% of the doses used in the two drug combination studies, the objective of this dose escalation study was to evaluate the safety/tolerability of DMV until the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) could be identified. Efficacy was also evaluated. Methods: Patients with relapsed/refractory MM and progressive disease requiring treatment were enrolled in the study. Dose level 1 consisted of D 10 mg/m2 and M 5 mg/m2 given IV on day 1 with V given by IV push on days 1, 4, 8, and 11. Cycles were repeated every 28 days up to a maximum of 6 cycles. Dose levels of D, M, V (mg/m2) in the subsequent three cohorts were (10, 10, 0.7), (20, 10, 0.7), and (20, 10, 1.0) respectively. Once the MTD has been identified, an additional 17 patients will be enrolled at this dose level in the phase II portion of the study. Results: 5 patients (2 males, median age 65, range 33–79) have been enrolled in the study thus far. The myeloma subtypes include 2 IgG, 1 IgA, and 2 with light chains only. In this heavily pretreated population (range 2–7 prior therapies), 4 patients received prior autologous stem cell transplantation, 2 had a prior nonmyeloablative allogenic transplant, 4 prior VAD, 1 prior bortezomib, 2 prior oral melphalan, 3 prior thalidomide, 2 prior CC-5013, and 2 prior spinal radiation. The first dose cohort has been completed without any DLT. One patient had 3 days of Grade 3 neutropenia. All other toxicities were Grade 1–2 including asthenia, vomiting, thrombocytopenia, and headache. Of note, a patient with baseline Grade 2 peripheral neuropathy and on hemodialysis remained stable. A patient with Grade 2 chronic graft versus host disease also remained stable. Four patients have been enrolled at dose level one. One patient, who had progressive disease after an autologous and a nonmyeloablative allogenic transplant as well as CC5013, had a near CR (IFE+) after the second cycle of DMV. Two patients have had stable disease. One had disease progression after one cycle and subsequently died. The patient on dose level two is too early to evaluate. Conclusion: Thus far, DMV appears to be well tolerated and no DLT has been observed even in elderly patients with significant comorbidities. The finding of a near CR and SD at only dose level 1 is encouraging particularly since the patients were significantly pretreated. Dose escalation continues to determine the MTD.

Dose Escalation Study To Evaluate Dose Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD) and Safety of Alemtuzumab for Consolidation Therapy in Patients with Chronic Lymphoycytic Leukemia: Phase I/II Trial of the German CLL Study Group (GCLLSG).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2053-2053 ◽  
Author(s):  
Kirsten Fischer ◽  
Carmen D. Schweighofer ◽  
Matthias Ritgen ◽  
Sebastian Boettcher ◽  
Elena Scharf ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Partial Remission ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Infection Prophylaxis ◽  
Dose Escalation Study

Abstract Introduction: Alemtuzumab has shown considerable activity in both relapsed/refractory chronic lymphocytic leukemia (CLL) and frontline treatment setting. In a prior randomised phase III trial we have demonstrated that consolidation with alemtuzumab significantly improves progression-free survival and the rate of molecular remissions in CLL patients after fludarabine based chemotherapy. However, significant toxicity including severe infections were observed. This ongoing phase I/II trial investigates the maximum tolerated dose (MTD) of alemtuzumab consolidation in patients with CLL after 2nd line chemotherapy. Methods: 12 patients (pts) in complete or partial remission after induction chemotherapy with either fludarabine plus cyclophosphamide (FC) or fludarabine plus cyclphosphamide plus rituximab (FCR) were eligible to receive alemtuzumab consolidation 90 to 150 days after last chemo infusion. Alemtuzumab was administered in 2 different cohorts either intravenously (iv, cohort A) or subcutaneously (sc, cohort B), once weekly for 8 weeks. Dose escalation was started with 10 mg iv/sc and increased in 10 mg intervals per dose level, each dose level including a minimum of 3 pts. All pts received standard premedication and infection prophylaxis. Blood samples were taken to determine pharmacokinetics in week 4 and 8. MRD was evaluated in peripheral blood and bone marrow by 4-colour flow cytometry at week 8 and 3-monthly thereafter. Results: 10 pts (median age 68 years) in complete or partial remission (1 CR, 1 nPR, 8 PR) after FC/FCR were treated with alemtuzumab in cohort A. Due to 2 dose limiting toxicities (DLT) at dose level 2 (20 mg iv, 1 FUO requiring iv antibiotics, 1 exacerbated erythema exsudativum multiforme) the MTD of alemtuzumab was determined at 10 mg iv. In cohort B, so far 2 patients (1 CR, 1 PR) have been treated with 10 mg alemtuzumab sc and no DLT has been observed. Besides the 2 DLT overall toxicity was tolerable in both cohorts with 8 CTC grade III cytopenias reversible in less then 2 weeks, 1 FUO and 2 subclinical CMV reactivations. All infections were successfully treated. After the last dose of alemtuzumab (week 8) the clinical response status of 4 pts converted from PR to CR. Up to a median follow up of 22 months 3 pts presented with PD, 2 of them died due to disease progression. MRD negativity (< 1 × 10E-4) was achieved in 3/10 pts in cohort A and 1/2 pts in cohort B. The median PFS of all pts was 19.9 months. For the majority of patients examined alemtuzumab plasma concentrations in week 4 and 8 showed rapid accumulation with stable levels after administration in the range of 100 to 300 ng/ml. Conclusion: Consolidation with alemtuzumab in CLL pts after 2nd line therapy is safe and able to achieve response improvement including MRD negativity. Dose escalation of alemtuzumab has determined a MTD of 10 mg, if administered intravenously. Ongoing trial activity is attempting to determine the MTD, pharmacokinetic and clinical efficacy of subcutaneous alemtuzumab consolidation.

Phase I study of BPM 31510 in advanced solid tumors: Updated analysis of a novel treatment with promising activity.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3015-3015
Author(s):  
Andrew Eugene Hendifar ◽  
Sant P. Chawla ◽  
Doris Quon ◽  
Victoria S Chua ◽  
Lita Fernandez ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Minor Response ◽  
Grade 3

3015 Background: BPM 31510 is a novel small molecule that targets the metabolic machinery of the cancer microenvironment to reverse the aerobic glycolytic phenotype of cancer cells. Effector downstream signaling results in re-capitulation of BCL-2 mediated apoptosis and disruption in tumor vasculature by modulation of VEGF. (NR Narain et al., Proceedings of AACR Meeting Abstracts 2011). Methods: A standard 3+3 phase I, dose-escalation study design was used in patients with advanced solid tumors refractory to standard treatment. Primary objectives were establishment of the maximum tolerated dose (MTD) and safety/pharmacokinetic (PK) correlates. Secondary objectives included exploratory pharmacodynamics (PD) and preliminary efficacy (RECIST-1.1) of BPM 31510 in sequential cohorts of 3 to 6 pts. Results: At time of submission, 34 patients with advanced cancer who had failed multiple chemotherapeutic regimens had been enrolled in 7 dose cohorts (ranging from 5.6 mg/kg to 78.2 mg/kg). Patients received a median of 2 cycles (1-7). 2 patients have had grade 3 elevation in PT/INR, otherwise there have been no grade 3/4 treatment related toxicities to date. The pharmacokinetics of BPM 31510 are linear and there were no sex differences in the parameters normalized by dose and body surface area. Tmax and Cmax are associated with the end of the infusion. The values for t1/2 ranged from 2.18 to 13.3 hr, with little or no dependence of t1/2 on dose. Objective tumor responses have been noted at the dose of 58.6mg/kg with 1 partial response (myxoid liposarcoma) and 1 minor response (pleomorphic sarcoma). Six patients (19%) have had disease stabilization (> 4 months). Conclusions: Interim data from this phase I study indicate that BPM 31510 is well tolerated with no dose limiting toxicities to date. A partial response and minor response were observed and correlates with dose escalation. Taken together, there is strong rationale for further clinical development of this compound as an anti-cancer agent.

A phase I study of Debio 0932, an oral HSP90 inhibitor, in patients with solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3026-3026 ◽  
Author(s):  
Nicolas Isambert ◽  
Antoine Hollebecque ◽  
Yann Berge ◽  
Hein van Ingen ◽  
Silvano Brienza ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Hsp90 Inhibitor ◽  
Treatment Withdrawal ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study

3026 Background: Debio 0932 is an oral second-generation heat shock protein 90 (HSP90) inhibitor that has shown extended tumor retention, blood-brain-barrier penetration, and promising anti-tumor activity both as monotherapy and combination against a broad range of tumors in pre-clinical models. Here we report the results of the dose escalation part of a phase I study in patients with advanced solid tumors or lymphoma (NCT01168752). Methods: This was an open-label, non-randomized, 3 + 3 dose-escalation study to determine the maximum tolerated dose (MTD) of Debio 0932 when given QD or Q2D during the first 30 days of treatment in patients with advanced solid tumours or lymphoma resistant to standard therapy. The starting dose in both treatment groups was 50mg. Doses were increased according to an algorithm based on observed toxicity and dose limiting toxicities (DLT). Tumor assessments were performed every 8 weeks. Results: Patient characteristics and results are summarized below. DLTs occurred at 1600mg in both dose groups. Adverse events (AE) were mostly CTCAE grade 1 or 2, with no apparent dose relationship. No ocular or cardiac toxicity was observed. The main reason for treatment withdrawal was progressive disease. Investigator-reported cases of SD and PR were observed. Conclusions: Debio 0932 mono-therapy was generally well tolerated and showed promising signs of efficacy in patients with advanced solid tumors. The recommended phase II dose, established at 1000mg QD, will be tested in an additional 30 patients in an ongoing expansion study. A phase I-II study of Debio 0932 in combination with standard of care in the first- and second-line treatment of NSCLC is planned. [Table: see text]

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