Phase I trial of Seneca Valley Virus (NTX-010), a newly discovered systemically deliverable oncolytic picornavirus, in patients with solid tumors with neuroendocrine features

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18014-18014
Author(s):  
C. M. Rudin ◽  
D. Lansey ◽  
K. D. Burroughs ◽  
L. M. Hales ◽  
J. R. Neefe ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Metastatic Cancer ◽  
Cell Cancer ◽  
Safety Data ◽  
Small Cell ◽  
Low Grade ◽  
Viral Kinetics ◽  
Xenograft Models

18014 Background: NTX-010 is a replication-competent cytolytic picornavirus with selective tropism for cancers with neuroendocrine features. NTX-010 mediates high selective cytotoxicity for tumor cells with neuroendocrine properties and has no cytotoxicity on any human adult cell type tested. Antitumor efficacy has been demonstrated in 11/11 xenograft models, including metastatic, orthotopic, and syngeneic models. Intravenous (IV) administration of doses as low as 107 vp/kg are effective in xenograft models of small cell lung cancer. No significant toxicity in animals is seen at doses up to 1013 vp/kg. Methods: We initiated a single dose administration phase I dose-escalation study in patients with advanced solid tumors with neuroendocrine markers (CD56+, synaptophysin+, or chromogranin A+), starting at 107 vp/kg IV over 1h. Planned dose escalation is in log increments. Results: The first dose cohort has been completed, with no dose-limiting toxicities observed. Low grade fever, chills, arthralgias and myalgias starting 3 - 4 days after virus administration and lasting less than a week have been noted. The first study subject, with a widely metastatic small cell cancer with bladder invasion, demonstrated viral replication in vivo peaking d4 with >10,000-fold amplification of the input dose. This subject had complete clearance of infectious virus by day 17, but persistence of viral RNA detectable by RT-PCR in blood and urine until the time of her death from metastatic cancer on day 28. Autopsy demonstrated extensive intratumoral necrosis, and immunohistochemistry confirmed the presence of NTX-010 capsid protein in liver metastases but not adjacent normal liver. Conclusions: NTX-010 is a novel first-in-class anticancer virus with selective tropism for tumors with neuroendocrine features. This is the first anticancer virus given intravenously with documented selective intratumoral infection and replication. Administration was well tolerated. Safety data and viral kinetics will be presented. No significant financial relationships to disclose.

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.

Final results: A dose escalation phase I study of ARQ 197, a selective c-Met inhibitor, in patients with metastatic solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3548-3548 ◽  
Author(s):  
T. Mekhail ◽  
T. Rich ◽  
L. Rosen ◽  
F. Chai ◽  
Z. Semic-Suka ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Safety Data ◽  
Dose Escalation Study ◽  
Tumor Cell Migration ◽  
Drug Concentrations ◽  
Arq 197 ◽  
Favorable Safety

3548 Background: ARQ 197 is a selective, non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell migration, invasion, and proliferation. Methods: This phase I dose escalation study enrolled patients (pts) with metastatic solid tumors to determine the drug's safety profile, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics (PK), and preliminary antitumor activity. Dose escalation followed an accelerated titration design and was modified to the traditional escalation design (3+3 pts) once grade 2 toxicity was observed. ARQ 197 was initially administered orally twice daily (BID) for 2 weeks followed by 1 week off and then modified to evaluate continuous BID dosing based on favorable safety data. Intra-patient dose-escalation was allowed in this study. Additional pts were enrolled and treated at the 360 mg bid continuous dose, which was determined to be the RP2D in another phase I clinical trial. Results: To date, 65 pts (38 male/27 female; median age 61; 9 colon/colorectal, 8 renal cell carcinoma/kidney, 6 ovarian, 6 sarcoma, 5 lung cancer and 31 others) have been treated at 11 dose levels (10 mg bid to 360 mg bid). All treated pts achieved plasma drug concentrations significantly above in vitro IC50 values. The most common drug-related adverse events (AEs) were fatigue (18.5%) and nausea (12.3%). One case each of the following drug-related serious AEs were reported in 4 pts: anemia, leukopenia, neutropenia, thrombocytopenia, dehydration, liver failure, abdominal pain, nausea, and vomiting. Three pts with neuroendocrine, prostate, or testicular cancer achieved a partial response (PR), 32 demonstrated stable disease (SD) and 13 progressed. The 3 PR pts were initially treated at 10, 40 or 90 mg BID respectively. Their doses were escalated to 50, 70, or 120 mg BID respectively after 18 to 33 weeks on treatment. An overall response rate of 6.3% and a disease control rate (CR+PR+SD) of 72.9% were demonstrated among 48 pts who are evaluable for efficacy. Conclusions: ARQ 197 has demonstrated a favorable safety profile up to the dose of 360 mg bid. Preliminary evidence of anti-cancer activity was observed. Final study data on drug safety, PK and efficacy will be presented. [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.

A phase I dose-escalation study of the MDM2-p53 antagonist BI 907828 in patients (pts) with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3016-3016
Author(s):  
Patricia LoRusso ◽  
Mrinal M. Gounder ◽  
Manish R. Patel ◽  
Noboru Yamamoto ◽  
Todd Michael Bauer ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Geometric Mean ◽  
Dose Range ◽  
Low Grade ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study

3016 Background: BI 907828, a highly potent and orally administered MDM2-p53 antagonist, showed antitumor efficacy in vivo, especially in TP53 wild-type MDM2-amplified de-differentiated liposarcoma (DDLPS) patient-derived xenografts and syngeneic models. Methods: NCT03449381 is a phase I study of BI 907828 in pts with solid tumors. The objectives of the dose-escalation part were to determine the maximum tolerated dose (MTD) based on the frequency of pts with dose-limiting toxicities (DLTs) during cycle 1, determine the recommended dose for expansion, and evaluate the safety and tolerability of two dosing schedules: BI 907828 given on day 1 of 21-day cycles (Arm A) or days 1 and 8 of 28-day cycles (Arm B). Dose escalation was guided by a Bayesian logistic regression model. The secondary objectives include pharmacokinetics (PK), pharmacodynamics and antitumor activity. Results: At January 15, 2021, 54 pts with advanced solid tumors (median of 2 lines of prior systemic therapies; range 0–11) were treated with BI 907828 (Arm A, 29 pts, dose range 10–80 mg; Arm B, 25 pts, dose range 5–60 mg). In Arm A, 5 pts experienced DLTs in cycle 1, including one Grade (Gr) 3 Nausea and one Gr 3 Thrombocytopenia at 45 mg, one Gr 3 Enterocolitis at 60 mg, and one Gr 4 Neutropenia and one Gr 4 Thrombocytopenia at 80 mg. In Arm B, 3 DLTs were reported: one Gr 4 Thrombocytopenia at 45 mg, one Gr 4 Neutropenia associated with Gr 4 Thrombocytopenia, and one Gr 3 Neutropenia at 60 mg. The most common Gr 3/4 treatment-related adverse events (AEs) were Thrombocytopenia (28.6%), Neutropenia (10.7%) and Nausea (10.7%) in Arm A, and Thrombocytopenia (16.6%) and Neutropenia (12.5%) in Arm B. Preliminary PK data indicate that BI 907828 reaches Tmax at 4–6 h. Mean plasma exposures (Cmax and AUC0-inf) increased with dose. The geometric mean (gMean) Clearance/F was 5–19 mL/min and the gMean apparent volume of distribution was 23–57 L. The gMean half-lives estimated after the 1st dose were 26–55 h. Inter-patient variability in exposure was moderate. An increase in the target engagement biomarker GDF-15 in plasma was observed. The mean fold-change from baseline ranged from 8 to 49. Antitumor activity was seen in both schedules. In Arm A, a confirmed PR was seen in 2 pts with MDM2-amplified LPS (one PR lasted > 2 years) and SD in 17 pts. In Arm B, 2 pts had PR (one confirmed in MDM2-amplified LPS and one not yet confirmed in MDM2-amplified pancreatic adenocarcinoma) and 14 had SD. Of note, 5 of 10 pts with DDLPS were progression-free for ≥9 months. Conclusions: BI 907828 showed a manageable safety profile, favorable PK properties and early signs of efficacy, especially in MDM2-amplified tumors. With both dosing regimens, DLTs were Neutropenia and Thrombocytopenia. Non-hematologic AEs, mainly gastrointestinal, were mostly low-grade and not dose-limiting. The MTD of 60 mg in Arm A (day 1 of 21-day cycles) and 45 mg in Arm B (days 1 and 8 of 28-day cycles) are awaiting confirmation. Clinical trial information: NCT03449381.

Phase I safety and tolerability of once daily oral afatinib (A) in combination with docetaxel (D) in patients (pts) with relapsed or refractory advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13010-e13010
Author(s):  
Helene Senellart ◽  
Jaafar Bennouna ◽  
Nicolas Isambert ◽  
Helene De-Montserrat ◽  
Patrick J. Squiban ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Dose Range ◽  
Safety Data ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Once Daily ◽  
Expansion Cohort ◽  
Initial Starting

e13010 Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open label, Phase I, dose escalation trial investigated the safety, tolerability, and PK of A, in two parallel dose cohort expansion parts, in combination with either gemcitabine (Part A) or D (Part B) in patients with relapsed or refractory solid tumors. Preliminary results from Part B are presented here. Methods: Eligible pts (confirmed diagnosis of advanced solid tumors, ECOG PS 0–1) received once daily, oral dosing of A in combination with D, given iv on Day 1 of every 3 week cycle. Dosing of A started on Day 2 of Cycle 1. Primary objective was to establish the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLT) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 pts using a 3+3 design. Initial starting dose level was A 30 mg/day and D 60 mg /m², escalating up to A 50 mg/day and D 75 mg/m² until the MTD was reached, and followed by a PK expansion cohort of 12 pts at the MTD level. Incidence and severity of AEs were recorded. Results: To date, 21 pts have been treated with A (30–50 mg/day) and D (60–75 mg/m2), with baseline characteristics: mean age (55.4 years), women (42.9%) and number of prior chemotherapies (≤2: 57%; >2: 43%). Fourteen pts received 2–4 cycles of treatment and five patients received 4 or more cycles. In Cycle 1, DLT was experienced by one out of six pts receiving 30 mg afatinib + 60 mg/m² docetaxel (Grade 3 diarrhea). No DLT was observed during the subsequent dose levels up to A 50 mg/day and D 75 mg/m². AEs observed in most pts were diarrhea (76.2%) and asthenia (66.7%). Conclusions: In pts with relapsed or refractory advanced solid tumors, the combination of A and D is well tolerated. AEs were manageable and the MTD was not reached in the tested dose range up to A 50 mg/day and D 75 mg/m². Considering the potential for diarrhea and rash during later cycles, the recommended dose for the expansion cohort was A 40 mg/day in combination with D 75 mg/m². Enrollment is ongoing (nine pts to date) and additional safety data and preliminary evidence of activity are anticipated to be available at the time of presentation.

A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2523-2523 ◽  
Author(s):  
Howard A. Burris ◽  
Manish R. Patel ◽  
Daniel C. Cho ◽  
Jeffrey Melson Clarke ◽  
Martin Gutierrez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Solid Tumors ◽  
Metastatic Cancer ◽  
Low Grade ◽  
Phase 2 ◽  
Dose Escalation Study ◽  
Phase 2 Clinical Trial ◽  
Personalized Approach

2523 Background: T-cell targeting of mutation-derived epitopes (neoantigens) has been demonstrated to drive anti-tumor responses. Immunizing patients against such neoantigens in combination with a checkpoint inhibitor (CPI) may elicit greater anti-tumor responses than CPI alone. Mutations are rarely shared between patients, thus requiring a personalized approach to vaccine design. Methods: A phase I dose escalation study of mRNA-4157 as adjuvant monotherapy in patients with resected solid tumors (melanoma, bladder carcinoma, HPV negative HNSCC, NSCLC, SCLC, MSI-High, or TMB High cancers) and in combination with pembrolizumab in patients with advanced or metastatic cancer is being conducted to evaluate safety. mRNA-4157 is a lipid encapsulated personalized vaccine encoding multiple neoantigens selected using a proprietary algorithm designed to induce neoantigen specific T cells and associated anti-tumor responses. Patients may receive up to 9 cycles (Q3W) of mRNA-4157 by intramuscular injection (0.04 – 1 mg). In the combination arm, pembrolizumab (200 mg) is administered for two cycles prior to combination with mRNA-4157; patients may continue pembrolizumab after completion of 9 cycles of combination therapy. Primary end points include safety, tolerability, and recommended phase 2 dose. Results: 33 patients received mRNA-4157; 13 as monotherapy and 20 in combination with pembrolizumab. No DLTs were reported, and treatment related AEs have generally been of low grade and reversible, and no drug related SAEs or AEs ≥ grade 3 have been observed. Of the 13 patients on adjuvant monotherapy (3 melanoma, 8 NSCLC, 2 MSI-High), 12 patients remain disease free on study, median follow-up of 8 months. 20 patients have been treated in combination (1 TMB-high, 4 bladder, 2 HNSCC, 1 melanoma, 7 NSCLC, 2 SCLC, 3 MSI-high), 12 had progressed on prior CPI, 16 have been restaged and there are 1 CR (on pembrolizumab prior to vaccination), 2 PR, 5 SD for at least 5 combination cycles, 5 PD, 2 iuPD, and 1 patient is non-evaluable for response but remains on study. Neoantigen specific T cell responses have been detected by IFN-γ ELISpot from PBMCs. Conclusions: mRNA-4157 is safe and well tolerated at all dose levels tested. Clinical responses have been observed in combination with pembrolizumab and neoantigen-specific T cells have been induced, supporting the advancement of mRNA-4157 to phase 2. Clinical trial information: NCT03313778.

A phase 1 study of SGN-B6A, an antibody-drug conjugate targeting integrin beta-6, in patients with advanced solid tumors (SGNB6A-001, Trial in Progress).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3144-TPS3144
Author(s):  
Amita Patnaik ◽  
Emiliano Calvo ◽  
Sarina Anne Anne Piha-Paul ◽  
Antoine Hollebecque ◽  
Vladimir Galvao ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Squamous Cell Cancer ◽  
Phase 1 ◽  
Cell Cancer ◽  
Small Cell ◽  
Advanced Solid Tumors ◽  
Small Cell Lung ◽  
Antibody Drug Conjugate ◽  
Antibody Drug

TPS3144 Background: The extracellular matrix (ECM) plays an important role in solid tumor pathogenesis and is a major focus of research and therapeutic targeting. Integrin beta-6 is a cell surface receptor that interacts with the ECM to mediate cellular adhesion. Integrin beta-6 is overexpressed in numerous solid tumors and its expression is a negative prognostic marker in cancers including colorectal, non-small cell lung, gastric, and cervical cancers. SGN-B6A is an investigational vedotin, an antibody-drug conjugate directed against integrin beta-6 to selectively deliver the cytotoxic agent monomethyl auristatin E, which binds tubulin and induces apoptosis. In multiple xenograft models, treatment with SGN-B6A resulted in tumor growth delay and regression in tumor volume when compared to non-binding control. Methods: SGNB6A-001 (NCT04389632) is a phase 1, first-in-human, open-label, multicenter study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN-B6A in adults with select advanced solid tumors. Primary objectives are to evaluate the safety and tolerability of SGN-B6A in patients with advanced solid tumors, identify the maximum tolerated dose, and identify a recommended dose and schedule. The study has 2 parts: dose escalation (Part A) and dose expansion with multiple disease-specific cohorts and a biology cohort (Part B). SGN-B6A will initially be given by intravenous infusion on Days 1, 8, and 15 of 21-day cycles. The dose escalation (Part A) will be conducted using the modified toxicity probability interval method to determine a dose that demonstrates a dose-limiting toxicity rate of 25% with a 5% margin. The dose and schedule for Part B will be determined based on evaluation of safety, PK, and pharmacodynamic biomarkers. Response evaluations will be based on RECIST v1.1. Patients must be ≥18 years old and have histologically or cytologically confirmed metastatic or unresectable solid malignancy within one of the following tumor types: non-small cell lung cancer, head and neck squamous cell cancer, breast cancer, esophageal cancer, ovarian cancer, cutaneous squamous cell cancer, exocrine pancreatic adenocarcinoma, bladder cancer, cervical cancer, or gastric cancer. After an appropriate dose and schedule are determined in Part A, safety and preliminary antitumor efficacy of SGN-B6A will be evaluated in indication-specific cohorts (Part B). This study is ongoing in sites across North America and Europe. Clinical trial information: NCT04389632.

scholarly journals Phase I Dose Escalation, Pharmacokinetic and Pharmacodynamic Study of Naptumomab Estafenatox Alone in Patients With Advanced Cancer and With Docetaxel in Patients With Advanced Non–Small-Cell Lung Cancer

2009 ◽  
Vol 27 (25) ◽  
pp. 4116-4123 ◽  
Author(s):  
Hossein Borghaei ◽  
Katherine Alpaugh ◽  
Gunnar Hedlund ◽  
Göran Forsberg ◽  
Corey Langer ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Dose Escalation ◽  
Liver Toxicity ◽  
Cell Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Fragment Antigen Binding

Purpose Two phase I studies were conducted of ABR-217620 alone or in combination with docetaxel. This is a recombinant fusion protein consisting of a mutated variant of the superantigen staphylococcal enterotoxin E (SEA/E-120) linked to fragment antigen binding moiety of a monoclonal antibody recognizing the tumor-associated antigen 5T4. Patients and Methods Patients with non–small-cell lung cancer (NSCLC), pancreatic cancer (PC), and renal cell cancer (RCC) received 5 daily boluses of ABR-217620 (3-month cycles) in escalating doses to determine the maximum-tolerated dose (MTD; ABR-217620 dose escalation monotherapy [MONO] study). Doses were selected based on individual patient anti–SEA/E-120 titers pretreatment. Patients with NSCLC received 4 daily, escalating doses of ABR-217620 followed by docetaxel in 21-day cycles (ABR-217620 dose escalation combination with docetaxel [COMBO] study). Results Thirty-nine patients were enrolled in the MONO study and 13 were enrolled in the COMBO study. The monotherapy MTD was 26 μg/kg (NSCLC and PC) and 15 μg/kg (RCC). Dose-limiting toxicities (DLTs) in the MONO study were fever, hypotension, acute liver toxicity, and vascular leak syndrome. In the COMBO study, the MTD was 22 μg/kg (neutropenic sepsis). Adverse events included grade 1 to 2 fever, hypotension, nausea, and chills. Treatment caused a systemic increase of inflammatory cytokines and selective expansion of SEA/E-120 reactive T-cells. Tumor biopsies demonstrated T-cell infiltration after therapy. Fourteen patients (36%) had stable disease (SD) on day 56 of the MONO study. Two patients (15%) in the COMBO study had partial responses, one in a patient with progressive disease on prior docetaxel, and five patients (38%) had SD on day 56. Conclusion ABR-217620 was well tolerated with evidence of immunological activity and antitumor activity.

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