First-in-human dose escalation of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2547-2547
Author(s):  
Justin C Moser ◽  
Mark Voskoboynik ◽  
Nehal J. Lakhani ◽  
Michael Millward ◽  
Diwakar Davar ◽  
...  
Keyword(s):  
T Cell ◽  
Colorectal Carcinoma ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Low Grade ◽  
Checkpoint Inhibition ◽  
Human Dose ◽  
Cd28 Costimulation ◽  
Advanced Malignancies ◽  
Dose Levels

2547 Background: Strong preclinical rationale has emerged for combining checkpoint inhibition (CPI) with T cell costimulatory agonists, particularly CD28, a critical T cell costimulatory molecule recently recognized as a key target of checkpoint inhibition. ALPN-202 is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. It has demonstrated superiority to CPI-only therapies in tumor models, while demonstrating favorable safety in preclinical toxicology studies. Methods: This is a cohort-based, open-label dose escalation and expansion study of ALPN-202 in adults with advanced solid tumors or lymphoma (NCT04186637). Subjects with cancers refractory to standard therapies (including approved CPIs), or cancers without available standard or curative therapy are eligible. After two planned single-subject cohorts, a standard 3+3 dose escalation has been implemented with two dose schedules in parallel, Q1W and Q3W. Objectives include evaluation of safety and tolerability, PK, PD and preliminary anticancer activity of ALPN-202. Disease assessments are evaluated by RECIST v1.1 for solid tumors or by Lugano Classification for lymphoma. Results: As of January 2021, 20 subjects with advanced malignancies have received ALPN-202. Dose-dependent PK and target saturation have been preliminarily observed. So far, ALPN-202 has been well tolerated at dose levels ranging from 0.001 to 1 mg/kg weekly, with no DLTs. Low-grade skin toxicities (grade 1-2 rash) have been observed in 4 subjects (20%). Among 11 evaluable subjects, an unconfirmed partial response has been observed in one subject with colorectal carcinoma, while stable disease has been observed in 5 subjects with colorectal carcinoma, mesothelioma (2), cholangiocarcinoma, and renal cell carcinoma -- for a preliminary clinical benefit (PR+SD) rate of 100% (4/4) at dose levels of 0.3 mg/kg and higher, or 54% (5/11) overall (table). The meeting presentation will update this data, which is expected to include the conclusion of Q1W dose escalation, as well as immune correlates. Conclusions: First-in-human dose escalation with ALPN-202 has been well tolerated at doses capable of engaging CD28 costimulation in vivo in association with dual PD-L1/CTLA-4 checkpoint inhibition, with early signs of anti-tumor activity. These findings suggest that CD28 agonism can be safely achieved in humans, and further suggest that dose expansion with ALPN-202 is warranted to assess the relevance of controlled CD28 costimulation as a novel approach to cancer immunotherapy. Clinical trial information: NCT04186637. [Table: see text]

Phase I experience with first in class TnMUC1 targeted chimeric antigen receptor T-cells in patients with advanced TnMUC1 positive solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14513-e14513
Author(s):  
Rodolfo Gutierrez ◽  
Payal D Shah ◽  
Omid Hamid ◽  
Alfred L. Garfall ◽  
Avery Posey ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Solid Tumors ◽  
Chimeric Antigen Receptor ◽  
Dose Escalation ◽  
Intracellular Signaling ◽  
Antigen Receptor ◽  
Low Grade ◽  
Gi Symptoms ◽  
Dose Levels

e14513 Background: MUC1 is a glycoprotein that is expressed in healthy tissues on the luminal surface of simple and glandular epithelium. In tumors that arise from these cells, an alternate form with aberrant glycosylation is frequently over expressed and distinguishes tumor associated TnMUC1 from normal MUC1. We have generated a novel chimeric antigen receptor (CAR) targeting the TnMUC antigen comprised of a mouse anti-human scFv derived from the monoclonal antibody 5E5 which recognizes the epitope comprising Tn glycan of MUC1, a CD8a transmembrane region and dual CD2 and CD3z intracellular signaling domains. CD2 signaling in T-cells has been demonstrated to result in delayed exhaustion. The novel incorporation of this co-stimulatory domain may lead to enhanced persistence of the CART cells which is believed to be critical for efficacy in solid-tumors. Methods: This is a multi-center first in human Phase I study to evaluate the safety and preliminary efficacy of CART-TnMUC1-Cells for the treatment of solid-tumors. Solid-tumors included in the dose-escalation phase include metastatic treatment-resistant ovarian cancer (OC), pancreatic adenocarcinoma (PC), triple-negative breast cancer (TNBC) or non-small lung cancer (NSCLC). All patients must have TnMUC1 expression as determined by immunohistochemistry. Results: As of January 2021, a total of six patients were treated. Three in Cohort 1 (no lymphodepletion; dose = 1-2 x 107 TDN CART cells; tumors = 1 OC, 1 TNBC and 1 PC) and 3 in Cohort 2 (flu/cy lymphodepletion; dose = 1-2 x 107 TDN CART cells; tumors = 1 NSCLC and 2 OC). None of the patients treated experienced DLT’s. The trial is currently enrolling to Cohort 3 (flu/cy lymphodepletion, 5-6 x 107 TDN). No CRS, neurotoxicity, serious adverse reactions and no on-target/off-tumor toxicity was observed at these dose levels. The most common AE’s were low-grade GI symptoms (e.g., nausea, abdominal pain) in 5/6 patients (83.3%), generalized disorders (e.g., chills, fatigue) in 5/6 (83.3%) and hematologic disorders (e.g., anemia, neutropenia) in 3/6 (50%) of patients. CAR expansion was demonstrated in all patients and was improved in Cohort 2 following LD chemotherapy. Preliminary efficacy assessed by RECIST v1.1 at Day +28 demonstrate SD in all patients in Cohort 2. Conclusions: This is the first report of a novel CART-TnMUC1 construct containing a CD2 co-stimulatory domain that has been used in clinical trials for the treatment of refractory solid-tumor malignancies. While the study is still early in dose-escalation having completed only 2 of 6 planned dose levels there is no evidence of safety concerns or on-target/off-tumor toxicity. Additional safety, efficacy and biomarker data is currently being reviewed and will be presented. Clinical trial information: NCT04025216.

scholarly journals 523 Preliminary clinical experience with XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A553-A553
Author(s):  
Elaine Shum ◽  
Matthew Reilley ◽  
Yana Najjar ◽  
Adil Daud ◽  
John Thompson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Bispecific Antibody ◽  
Objective Response ◽  
Checkpoint Blockade ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Tumor Types

BackgroundXmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report updated data on patients treated at the recommended expansion dose from an ongoing, multicenter, Phase 1, dose-escalation and -expansion study of intravenous XmAb20717 in patients with selected advanced solid tumors that progressed after treatment with all standard therapies or with no standard therapeutic options.MethodsA maximum tolerated dose was not reached in dose escalation. XmAb20717 10 mg/kg every 2 weeks (Q2W) was selected as the expansion dose, based on consistent T-cell proliferation in peripheral blood indicative of dual PD-1/CTLA-4 checkpoint blockade, and response to treatment (RECIST[1.1]).1 Parallel expansion cohorts included ~20 patients each with melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and a basket of tumor types without an FDA-approved checkpoint inhibitor (CI). Patients treated with 10 mg/kg in dose escalation were pooled with expansion cohorts for analysis of clinical activity and safety.ResultsAs of 9 June 2021, 110 patients, ranging in age from 39 to 89 years and 66.4% male, were treated, and 5 were continuing treatment. Patients had received a median of 4 prior systemic treatment regimens, including CI therapy for 64.5%. The objective response rate was 13.0% (10/77 patients evaluable for efficacy), including 1 complete response (melanoma [confirmed]) and 9 partial responses (confirmed: 1 melanoma, 2 RCC, 2 CRPC, 1 ovarian cancer; unconfirmed: 1 melanoma, 2 NSCLC). The CRPC responders (2/7 with RECIST-measurable disease) had confirmed PSA decreases ≥ 50% from baseline (to 0.02 and 0.3 ng/mL); neither had progression on bone scans. All responders had prior CI exposure, except those with CRPC. Robust CD4 and CD8 T-cell activation was seen. Low baseline tumoral expression of myeloid recruitment genes, including IL-8, was associated with clinical benefit. Grade ≥ 3 immunotherapy-related adverse events in ≥ 3 patients included rash (16.4%), transaminase elevations (9.1%), hyperglycemia (4.5%), acute kidney injury (3.6%), amylase and lipase increased (2.7%), and lipase increased (2.7%).ConclusionsPreliminary data indicate 10 mg/kg XmAb20717 Q2W was associated with complete and partial responses in multiple tumor types and was generally well-tolerated in these heavily pretreated patients with advanced cancer. Changes in T-cell populations in the periphery and tumor are consistent with robust dual checkpoint blockade. These findings support further development of XmAb20717 in advanced solid tumors, including metastatic prostate cancer.Trial RegistrationNCT03517488ReferencesShum E, Daud A, Reilley M, et al. Preliminary safety, pharmacokinetics/pharmacodynamics, and antitumor activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors. JITC 2020;8(3):A247-8.Ethics ApprovalThe study was approved by each institution’s IRB.

P47.13 First-in-Human, Dose Escalation and Expansion Study of MT-6402 in Patients With PD-L1 Expressing Advanced Solid Tumors

2021 ◽  
Vol 16 (10) ◽  
pp. S1102
Author(s):  
D.R. Spigel ◽  
B. Anand ◽  
K. Carroll ◽  
J. Dekker ◽  
A. Georgy ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Advanced Solid Tumors ◽  
Human Dose

scholarly journals Phase I, First‐in‐Human, Dose‐Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Vorolanib in Patients with Advanced Solid Tumors

2018 ◽  
Vol 24 (4) ◽  
pp. 455 ◽  
Author(s):  
Johanna C. Bendell ◽  
Manish R. Patel ◽  
Kathleen N. Moore ◽  
Cynthia C. Chua ◽  
Hendrik‐Tobias Arkenau ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Human Dose

scholarly journals Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors

2020 ◽  
Vol 38 (19) ◽  
pp. 2140-2150 ◽  
Author(s):  
Jayesh Desai ◽  
Hui Gan ◽  
Catherine Barrow ◽  
Michael Jameson ◽  
Victoria Atkinson ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
First Generation ◽  
Objective Response ◽  
Reversible Inhibitor ◽  
Low Grade ◽  
Entire Study ◽  
Ras Mutations

PURPOSE Lifirafenib is an investigational, reversible inhibitor of B-RAFV600E, wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and efficacy of lifirafenib in patients with B-RAF– or K-RAS/N-RAS–mutated solid tumors. METHODS During dose escalation, adult patients with histologically/cytologically confirmed advanced solid tumors received escalating doses of lifirafenib. Primary end points were safety/tolerability during dose escalation and objective response rate in preselected patients with B-RAF and K-RAS/N-RAS mutations during dose expansion. RESULTS The maximum tolerated dose was established as 40 mg/d; dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade ≥ 3 treatment-emergent adverse events were hypertension (n = 23; 17.6%) and fatigue (n = 13; 9.9%). One patient with B-RAF–mutated melanoma achieved complete response, and 8 patients with B-RAF mutations had confirmed objective responses: B-RAFV600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAFV600E thyroid cancer/papillary thyroid cancer (PTC; n = 2), and B-RAFV600E low-grade serous ovarian cancer (LGSOC; n = 1). One patient with B-RAF–mutated non–small-cell lung cancer (NSCLC) had unconfirmed partial response (PR). Patients with K-RAS–mutated endometrial cancer and K-RAS codon 12–mutated NSCLC had confirmed PR (n = 1 each). No responses were seen in patients with K-RAS/N-RAS–mutated colorectal cancer (n = 20). CONCLUSION Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAFV600–mutated solid tumors, including melanoma, PTC, and LGSOC, as well as K-RAS–mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation B-RAF inhibitors and exploration of lifirafenib alone or as combination therapy in patients with selected RAS mutations who are resistant/refractory to first-generation B-RAF inhibitors are warranted.

Development of a Human Anti-CD27 Antibody with Efficacy in Lymphoma and Leukemia Models by Two Distinct Mechanisms

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2861-2861 ◽  
Author(s):  
Li-Zhen He ◽  
Larry Thomas ◽  
Jeffery Weidlick ◽  
Laura Vitale ◽  
Tom O'Neill ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Cell Lines ◽  
Lymphoid Cell ◽  
Lymphoblastic Leukemia ◽  
Tumor Challenge ◽  
Isotype Control ◽  
Human Lymphoid Cell ◽  
Dose Levels

Abstract Abstract 2861 CD27, a lymphoid cell-specific TNFR superfamily member, is constitutively expressed on the majority of T cells, some NK cells and memory B cells. Through interaction with its ligand CD70, CD27 transduces a co-stimulatory signal promoting T cell and NK cell activation and cytotoxicity. In addition, CD27 is also expressed on many lymphoid-originated hematological neoplastic cells, such as chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom macroglobulinemia, thus being a potential direct target for antibody therapy. To generate potential antibodies for clinical development, we immunized human Ig transgenic mice and developed a panel of CD27 specific human mAbs. Clone 1F5 was identified as a lead based on its high affinity to both human and monkey CD27, enhanced co-stimulation of T cells, and ADCC of CD27-expressing lymphoblastic cell lines. Using SCID mice challenged with CD27-expressing human lymphoid cell lines, we demonstrated that 1F5 mediates conventional antibody effector function. Compared to human IgG1 isotype control (huIgG1), 1F5 at doses ranging 33 μg – 500 μg (x 6) significantly delayed the growth of Burkitt's lymphoma Raji even when administration was initiated 1 week after tumor inoculation. Similar anti-tumor activity was observed against other CD27-expressing tumor lines including, Daudi and T-originated acute lymphoblastic leukemia CCRF-CEM. In order to investigate 1F5 in vivo agonistic activities and T cell-mediated tumor eradication, a human CD27 transgenic mouse model (hCD27-Tg) was generated and backcrossed onto C57BL/6 and BALB/c backgrounds. The expression profile and regulation of the human CD27 transgene driven by its own promoter were similar to that observed with endogenous mouse CD27. In addition to enhancing T cell responses when combined with vaccination, 1F5 treatment was highly effective against syngeneic mouse tumors including lymphoma BCL1 (BALB/c) and thymoma EL4-derived E.G7 (C57BL/6). For the BCL1 model, various dose levels of 1F5 mAb were delivered to mice intraperitoneally on days 3, 5, 7, 9 and 11 after i.v. administration of 107 BCL1 cells to huCD27 Tg and control animals. Controls including hCD27-Tg mice treated with saline or isotype control, or WT mice treated with 1F5 all performed consistently, leading to 50% survival approximately 23 days after tumor challenge. Treatment of mice with mAb, 1F5 substantially improved the 50% survival in a dose dependent fashion to >70 days post tumor challenge at the higher dose levels. Based on the promising efficacy data with anti-CD27 mAb 1F5 in immunocompromised and immunocompetent lymphoma models, a clinical grade product, referred to as CDX-1127 was manufactured and tested for safety. To assess the potential for 1F5 to mediate lymphocyte activation, we investigated its ability to induce proliferation and cytokine release from human PBMC or purified T cell cultures. Consistent with the known biology of CD27 we demonstrated the 1F5 mAb does not lead to direct activation of lymphocytes in the absence of additional signals. However, combining 1F5 with suboptimal levels of T cell receptor stimulation using anti-CD3 mAb (OKT3) was shown to enhance proliferation of human T cells. Two studies were performed using cynomolgus macaques. There were no CDX-1127 related mortalities or changes noted in the clinical condition, food appetence, body weights and body temperature, ophthalmic, electrocardiographic and clinical pathology assessments, organ weights and bone marrow assessments. In addition, there were no major differences in the percentage of lymphocyte populations between control and CDX-1127 treated animals at the end of the study demonstrating that the antibody did not significantly deplete normal CD27-expresssing cells. Based on the pre-clinical studies we are planning a Phase 1 clinical trial of CDX-1127 in patients with hematological malignancies and selected solid tumors. The trial is designed with separate arms to independently assess the safety and activity of CDX-1127 in hematologic malignancies, in which the antibody may act through multiple mechanisms, and in solid tumors where it would be fully dependent on indirect immune mechanisms. Disclosures: He: Celldex Therapeutics, Inc.: Employment. Thomas:Celldex Therapeutics, Inc.: Employment. Weidlick:Celldex Therapeutics, Inc.: Employment. Vitale:Celldex Therapeutics, Inc.: Employment. O'Neill:Celldex Therapeutics, Inc.: Employment. Prostak:Celldex Therapeutics, Inc.: Employment. Sundarapandiyan:Celldex Therapeutics, Inc.: Employment. Marsh:Celldex Therapeutics, Inc.: Employment. Yellin:Celldex Therapeutics, Inc.: Employment. Davis:Celldex Therapeutics, Inc.: Employment. Keler:Celldex Therapeutics, Inc.: Employment.

Clinical Safety and Activity in a Phase 1 Trial of IPI-145, a Potent Inhibitor of Phosphoinositide-3-Kinase-δ,γ, in Patients with Advanced Hematologic Malignancies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3663-3663 ◽  
Author(s):  
Ian W. Flinn ◽  
Steven M. Horwitz ◽  
Manish Patel ◽  
Anas Younes ◽  
James R. Porter ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Dose Levels

Abstract Abstract 3663 Introduction: Phosphoinositide-3-kinases (PI3Ks) play pivotal roles in cell signaling and regulate a variety of cellular functions relevant to oncogenesis. Impaired development and function of B and T lymphocytes has been demonstrated in PI3K-δ and PI3K-γ isoform knockout mice, supporting the development of PI3K-δ,γ specific inhibitors for B- and T-cell lymphoid malignancies. IPI-145 is a potent PI3K-δ,γ inhibitor in clinical development for patients (pts) with hematologic malignancies. The activity of IPI-145 via PI3K-δ and PI3K-γ isoform inhibition has been characterized in biochemical and cellular assays and demonstrated in preclinical models of B- and T-cell mediated disease. Early results of the Phase 1 study in pts with advanced hematologic malignancies are reported here. Methods and Patients: This Phase 1 dose-escalation study is designed to evaluate the safety, pharmacokinetics (PK) and activity of orally administered IPI-145 in pts with advanced hematologic malignancies, including T-cell lymphomas/leukemias. Sequential cohorts of pts are enrolled at progressively higher dose levels with expansion cohorts of pts with select hematologic malignancies. IPI-145 is administered orally 2 times per day (BID) continuously in 28-day cycles. Tumor response is evaluated based on disease-specific standard criteria. Results: As of 16 July 2012, the study had enrolled 20 pts; 5 pts with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), 4 with indolent non-Hodgkin's lymphoma (iNHL), 3 with aggressive B-cell NHL [including diffuse large B-cell lymphoma (DLBCL) n=2 and Richter's transformation n=1], 3 with multiple myeloma (MM), 2 with Hodgkin's lymphoma (HL), 2 with T-cell lymphoma [anaplastic large-cell lymphoma (ALCL) n=2] and 1 with mantle cell lymphoma (MCL). Of these pts, 11 are male and 9 female, with a median [range] age of 63 years [30–81], with 36% <6 month from most recent prior systemic therapy. The median [range] number of prior therapies was 3 [1–8]. IPI-145 doses administered include 8 mg BID (n=1), 15 mg BID (n=6), 25 mg BID (n=7), 35 mg BID (n=3), and 50 mg BID (n=3). The median [range] number of treatment cycles was 2 [1–8], with 12 (60%) pts continuing on treatment. Adverse events (AEs) have occurred in 13 (65%) pts, including 7 (35%) pts with AEs Grade ≥3. Treatment-related AEs occurred in 11 pts (55%) with Grade ≥3 occurring in 5 pts (25%). Grade 4 neutropenia was the one dose limiting toxicity observed to date (15 mg dose cohort). New Grade ≥3 hematological laboratory abnormalities included neutropenia [n= 6 (30%)] and thrombocytopenia [n= 1 (5%)]. Grade 3 ALT/AST elevations occurred in 1 (5%) MM pt with onset 6 weeks after IPI-145 initiation. Preliminary PK show dose-proportional increases in plasma Cmax and AUC over the dose range studied. Further, the PK and initial pharmacodynamic (PD) data from the first 3 cohorts (8–25 mg BID) predict continuous suppression of the PI3K-δ pathway with increasing inhibition of the PI3K-γ pathway with a 25 mg BID dose or greater. In the evaluable pts (n=11), responses were observed at the 8, 15, and 25 mg BID dose levels including 2/3 CLL/SLL pts (0 CR/2 PR/1 SD), 1/2 iNHL pts (1 CR/0 PR/1 SD), and 1/1 in MCL (1 PR). No responses have been observed to date in evaluable pts with MM (0/3) or aggressive NHL (0/2). All pts with at least SD after 2 cycles (n=6) remain on treatment including the first pt dosed. Based on the PK/PD and the preliminary activity observed in pts with CLL, iNHL and MCL, an expansion cohort is enrolling pts in these select hematologic diseases dosed at 25 mg BID to further evaluate the safety and preliminary activity of IPI-145. Dose escalation continues with a focus on pts with T-cell malignancies and DLBCL where increasing suppression of the PI3K-γ isoform may improve the efficacy profile. Additional expansion cohorts in T-cell lymphoma, DLBCL, myeloproliferative neoplasms and the acute leukemias will better define disease specific activity. Conclusions: IPI-145, an oral, potent PI3K-δ,γ inhibitor, appears to be well tolerated and has shown initial clinical activity in pts with iNHL, MCL, and CLL. A dose of 25 mg BID effectively inhibits PI3K-δ, providing a rationale for expansion in CLL/iNHL/MCL. Additional safety and efficacy data from the ongoing dose escalation evaluation in T-cell/aggressive NHL and the CLL/iNHL/MCL expansion cohort will be presented. Disclosures: Flinn: Infinity Pharmaceuticals, Inc.: Research Funding. Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc. : Research Funding. Patel:Infinity Pharmaceuticals, Inc. : Research Funding. Younes:Novartis: Honoraria, Research Funding; Celgene: Honoraria; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding; MIllenium: Honoraria; Incyte: Honoraria; Genentech: Research Funding; Infinity Pharmaceuticals, Inc. : Research Funding; Gilead: Research Funding. Porter:Infinity Pharmaceuticals, Inc. : Employment. Sweeney:Infinity Pharmaceuticals, Inc. : Employment. Allen:Infinity Pharmaceuticals, Inc. : Employment. Kelly:Infinity Pharmaceuticals, Inc. : Employment. Kahl:Infinity Pharmaceuticals, Inc. : Research Funding.

Phase I study of bortezomib and oxaliplatin (BOX) in solid tumors: Improved neurotoxicity (NT) profile with lower bortezomib (B) dose

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12007-12007
Author(s):  
R. A. Kosloff ◽  
J. Wright ◽  
P. Ivy ◽  
J. Escalon ◽  
B. Norwood ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Major Contributor ◽  
Organ Function ◽  
Dose Escalation Study ◽  
Adequate Organ Function ◽  
Dose Levels ◽  
Platinum Agents

12007 Background: B inhibits proteasome function and may be synergistic in causing apoptotic death with platinum agents. We were interested in combining B with OX but concerned with dose limiting (DL) NT based on our prior B phase I study [Hamilton et al., JCO 2005]: therefore this Phase I dose-escalation study (alternating increases of B and OX) focusing on NT was planned. Methods: Patients (pts) with metastatic solid tumors, PS 0–2, platinum or taxane naive, no peripheral neuropathy and adequate organ function, received B (D1, 4, 15, 18) and OX (D1, 15) every 28 days in a dose escalation design (see table ). Baseline and monthly assessments were performed by an independent neurologist. Results: 27 (18 gastrointestinal, 3 melanoma, 3 ovarian, 3 others) were accrued; pt characteristics: 14 male/13 female; median age 55 years (range 35–75); 2 median cycles (range 1–10). NT was not DL because it did not occur within the first cycle. Late and limiting NT was observed in levels 2–5 after 2–9 cycles, but serial neurologic evaluations showed reversible NT. With an amended new dose level to lower B to 1.0 mg/m2 (level 6) to avoid late NT, NT was not observed. Of 22 evaluable pts, there were 3 partial responses (ampullary, GE junction, biliary), 6 stable disease, and 13 disease progression by RECIST criteria. Conclusions: biweekly BOX is tolerable at B 1.0 mg/m2 and OX 85 mg/m2 with no DL NT. Additional observations on late NT are ongoing. This suggests B is a major contributor to NT observed in dose levels 2–5 and may potentiate the effects of OX. [Table: see text] [Table: see text]

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