1099 GBR 830: An OX40 antagonist antibody with a favorable toxicity profile in non-human primates

9502 Background: Neoadjuvant therapy (NT) for pts with clinical stage III melanoma remains an active area of research interest. Recent NT trial data demonstrates that achieving a pathologic complete response (pCR) correlates with improved relapse-free (RFS) and overall survival (OS). Checkpoint inhibitor (CPI) NT with either high or low dose ipilimumab and nivolumab regimens produces a high pCR rate of 30-45% but with grade 3-4 toxicity rate of 20-90%. In metastatic melanoma (MM), the combination of nivo with rela (anti Lymphocyte Activation Gene-3 antibody) has demonstrated a favorable toxicity profile and responses in both CPI-naïve and refractory MM. We hypothesized that NT with nivo + rela will safely achieve high pCR rates and provide insights into mechanisms of response and resistance to this regimen. Methods: We conducted a multi-institutional, investigator-initiated single arm study (NCT02519322) enrolling pts with clinical stage III or oligometastatic stage IV melanoma with RECIST 1.1 measurable, surgically-resectable disease. Pts were enrolled at 2 sites and received nivo 480mg IV with rela 160mg IV on wks 1 and 5. Radiographic response (RECIST 1.1) was assessed after completion of NT; surgery was conducted at wk 9 and specimens were assessed for pathologic response per established criteria. Pts received up to 10 additional doses of nivo and rela after surgery, with scans every 3 mo to assess for recurrence. The primary study objective was determination of pCR rate. Secondary objectives included safety, radiographic response by RECIST 1.1, event-free survival (EFS), RFS, and OS analyses. Blood and tissue were collected at baseline, at day 15, day 28, and at surgery for correlative analyses. Results: A total of 30 pts (19 males, median age 60) were enrolled with clinical stage IIIB/IIIC/IIID/IV (M1a) in 18/8/2/2 pts, respectively. 29 pts underwent surgery; 1 pt developed distant metastatic disease while on NT. pCR rate was 59% and near pCR ( < 10% viable tumor) was 7% for a major pathologic response (MPR, pCR + near pCR) of 66%. 7% of pts achieved a pPR (10-50% viable tumor) and 27% pNR (≥50% viable tumor). RECIST ORR was 57%. With a median follow up of 16.2 mos, the 1 -year EFS was 90%, RFS was 93%, and OS was 95%. 1-year RFS for MPR was 100% compared to 80% for non-MPR pts (p = 0.016). There were no treatment related gr 3/4 AEs that arose during NT; 26% of pts had a gr 3/4 AE that began during adjuvant treatment. Conclusions: Neoadjuvant and adjuvant treatment with nivo and rela achieved high pCR and MPR rates with a favorable toxicity profile in the neoadjuvant and adjuvant settings. Pts with MPR had improved outcomes compared to non-MPR pts. Translational studies to discern mechanisms of response and resistance to this combination are underway. Clinical trial information: NCT02519322.

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Cisplatin may be a Valid Alternative Approach in Ovarian Carcinoma with Carboplatin Hypersensitivity. Report of Three Cases

Tumori Journal ◽

10.1177/030089160308900315 ◽

2003 ◽

Vol 89 (3) ◽

pp. 311-313 ◽

Cited By ~ 11

Author(s):

Massimo Libra ◽

Roberto Sorio ◽

Angela Buonadonna ◽

Massimiliano Berretta ◽

Peter Stefanovski ◽

...

Keyword(s):

Ovarian Cancer ◽

Standard Treatment ◽

Chemotherapeutic Agent ◽

Advanced Ovarian Cancer ◽

Hypersensitivity Reactions ◽

Toxicity Profile ◽

Alternative Approach ◽

Successful Resolution ◽

Carboplatin Hypersensitivity ◽

Favorable Toxicity Profile

Platinum-based therapy is considered the standard treatment for patients with advanced ovarian cancer. Carboplatin has a more favorable toxicity profile than cisplatin; however, hypersensitivity reactions to carboplatin have been reported occasionally. We reviewed 112 cases of ovarian cancer treated with carboplatin at our institute to identify the hypersensitivity reactions to this chemotherapeutic agent. Hypersensitivity reactions were documented in nine cases (8%). No deaths occurred, but the reactions were judged severe in three of the 112 patients (2.6%). In our own experience with patients showing idiosyncrasy to carboplatin we observed successful resolution after retreatment with cisplatin. Since patients who relapse after initial treatment with carboplatin often respond to it a second time, it is important to continue this treatment.

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Favorable Toxicity Profile of Raltitrexed in Elderly Patients Treated for Colorectal Cancer: A Case Series

Gerontology ◽

10.1159/000071714 ◽

2003 ◽

Vol 49 (5) ◽

pp. 324-327 ◽

Cited By ~ 3

Author(s):

F. Franchi ◽

C. Pastore ◽

A. Caporale ◽

O. Fabiani ◽

L. Rossi ◽

...

Keyword(s):

Colorectal Cancer ◽

Elderly Patients ◽

Case Series ◽

Toxicity Profile ◽

Favorable Toxicity Profile

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Phase II Study of Oxaliplatin in Patients with Relapsed or Refractory Non-Hodgkin’s Lymphoma: Final Results.

Blood ◽

10.1182/blood.v104.11.2494.2494 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2494-2494

Author(s):

Yasuhiro Oki ◽

Peter McLauhlin ◽

Barbara Pro ◽

Frederick H. Hagemeister ◽

Archie Bleyer ◽

...

Keyword(s):

Cell Lines ◽

Phase Ii ◽

Performance Status ◽

Sensory Neuropathy ◽

Hodgkin's Lymphoma ◽

Entire Group ◽

Toxicity Profile ◽

Ecog Performance Status ◽

Non Hodgkin's Lymphoma ◽

Favorable Toxicity Profile

Abstract Many patients with NHL suffer from refractory or relapsed disease, and platinum-based combination therapy is widely used for salvage therapy. Oxaliplatin, a novel platinum derivative, is a more potent cytotoxic agent than cisplatin, demonstrating greater efficacy against many tumor cell lines, including lymphoma cell lines. Clinical studies of oxaliplatin for other malignancies have shown a favorable toxicity profile. The objective of this phase II trial was to investigate the activity of oxaliplatin in patients with relapsed or refractory non-Hodgkin’s lymphoma (NHL). Patients with measurable NHL who had experienced failure of one or more prior chemotherapy regimens were considered eligible. They were required to have an ECOG performance status £ 2 and adequate organ function. Patients were excluded if they had HIV infection, CNS lymphoma, or had chemotherapy or radiotherapy within 4 weeks prior to entering the study. All patients gave their written informed consent to participate. Oxaliplatin was administered at 130 mg/m2 every 21 days for up to six cycles in the absence of progression. Thirty-one patients (23 with aggressive NHL, 8 with indolent NHL) were enrolled on this trial. Thirty eligible patients received oxaliplatin, who were all assessable for toxicity. Response and survival were also analyzed in all 30 patients based on intention to treat analysis. The median patient age was 62 years, and most of the patients had an ECOG performance status of 0 or 1. The most common toxic effect was sensory neuropathy (87%). Grade 3 and 4 toxic effects included sensory neuropathy (10%), neutropenia (17%), and thrombocytopenia (20%). Objective responses occurred in 8 (27%) of the patients: 7 with aggressive NHL, 1 with indolent NHL. The median failure-free survival duration in the entire group, aggressive NHL group and indolent NHL group was 3.0, 2.1 and 4.0 months, respectively. It is noteworthy that three of the five patients with MCL (60%) had a significant response to oxaliplatin, including two CRus, with a median FFS duration of 5 months. When patient group is divided by IPI score (0/1 and 2 /3), the median FFS duration was 3.4 months and 2.6 months, respectively. Median response duration for entire group was 3.0 months. In summary, oxaliplatin has modest activity in patients with previously treated NHL, especially those with aggressive disease. The favorable toxicity profile of oxaliplatin warrants further investigation of it either in combination chemotherapy or with targeted biologic therapy.

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A phase I trial of PEGylated glutaminase (PEG-PGA) in combination with 6-diazo-5-oxo-L-norleucine (DON) in advanced, refractory, solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.14040 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 14040-14040

Author(s):

C. Mueller ◽

S. Al-Batran ◽

E. Jaeger ◽

M. Bausch ◽

N. Sethuraman ◽

...

Keyword(s):

Lung Cancer ◽

Treatment Duration ◽

Phase I Trial ◽

Small Cell ◽

Toxicity Profile ◽

Small Cell Lung ◽

Competitive Mechanism ◽

Grade 3 ◽

Tolerable Dose ◽

Favorable Toxicity Profile

14040 Background: Tumor cells are avid glutamine consumers and highly dependent on extracellular glutamine supply. Based on a competitive mechanism, the effectiveness of the glutamine analogue DON is enhanced if the available pool of glutamine is significantly (below 10% of baseline) depleted by PEG-PGA. Methods: The study was designed to determine the maximal tolerable dose (MTD) of DON in combination with PEG-PGA. The patients received intravenous PEG-PGA 120 I.U./m2 in combination with DON twice weekly for six weeks followed by a tumor assessment according to RECIST. DON dose was escalated from 5 to 185 mg/m2 using modified Fibonacci design and traditional 3-patient cohorts. Results: Fifty-eight pts (23f/35m) received at least 1 drug administration and were evaluable for the analysis. Median age was 62 (range 43–79) and median Karnofsky PS was 90% (range 70%-100%). Median treatment duration was 29 days (range 1–106). Nausea and vomiting represented the most common non-hematological grade 3 toxicities, being observed in 6.9% and 10.3% of pts, respectively. Hematological side effects were G4 leuco- and neutropenia (1.7%) and G3 thrombocytopenia (1.7%). The treatment was very well tolerated with all other grade 3 or 4 toxicities affecting less than 5% of patients. Forty-six pts were evaluable for efficacy. Stable disease was observed in 20 (43.5%) pts, including MR (>10%) in 5 (10.8%) pts. The efficacy was dose depended. Conclusions: The combination of PEG-PGA and DON is active and has a favorable toxicity profile. The MTD is now investigated in a Phase IIa trial in patients with refractory colorectal, renal or non small cell lung cancer. The accrual will be finished by January 2007. No significant financial relationships to disclose.

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Carboplatin versus cisplatin for the treatment of extensive-stage small cell lung cancer (SCLC): A National VA Database analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.9061 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 9061-9061

Author(s):

Ibrahim Azar ◽

Adam Austin ◽

Seongho Kim ◽

Hyejeong Jang ◽

Amit Chopra ◽

...

Keyword(s):

Performance Status ◽

Young Patients ◽

Standard Of Care ◽

Wald Test ◽

Toxicity Profile ◽

Current Standard ◽

Metastatic Setting ◽

Extensive Stage ◽

Ecog Ps ◽

Favorable Toxicity Profile

9061 Background: Current standard of care first line treatment for extensive stage SCLC includes combination of platinum-etoposide doublet with an immune checkpoint inhibitor. Carboplatin is preferred over cisplatin in the extensive stage disease because of its favorable toxicity profile. Data comparing the efficacy of carboplatin with cisplatin in the metastatic setting are limited. Methods: Data from the National VA Cancer Cube database were compiled. Only pathologically confirmed cases of extensive stage SCLC that received platinum-based multiagent chemotherapy were included. Interval-censored Weibull and Cox proportional hazard regression models were used to estimate median overall survival (OS) and hazard ratio (HR), respectively. Two survival curves were compared by a Wald test. Results: Overall, 2600 SCLC cases were studied: 1968 received carboplatin-based therapy (Carbo-SCLC) while 632 received cisplatin-based therapy (Cis-SCLC). Median OS of Carbo-SCLC and Cis-SCLC was 0.71 years (95% CI 0.68-0.75) versus 0.70 years (95% CI 0.64-0.76), respectively (HR = 0.99; 95% CI 0.90-1.10; p = 0.90). Median OS of patients with ECOG-PS of 0, 1, 2 and 3 was similar for Carbo-SCLC and Cis-SCLC. HR of death for Carbo-SCLC compared to Cis-SCLC stratified by performance status were: ECOG-PS 0: 1.04 (95% CI 0.78-1.38; p = 0.80); ECOG-PS 1: 0.87 (95% CI 0.71-1.06; p = 0.17); ECOG-PS 2: 0.92 (95% CI 0.69-1.24; p = 0.6); ECOG- PS 3: 1.13 (95% CI 0.66-1.92; p = 0.66). Multivariable regression analysis accounting for age and ECOG-PS shows a HR of 0.92 (95% CI 0.80-1.05; p = 0.24). Conclusions: Cisplatin-based chemotherapy was not associated with a survival advantage over carboplatin-based chemotherapy in extensive-stage SCLC., including in patients with robust performance status and young patients. The findings from this large dataset along with the favorable toxicity profile of carboplatin support its use as the platinum agent of choice in extensive stage SCLC.

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Dasatinib in Patients with Imatinib-Resistant Chronic Myeloid Leukemia: Experience from a Cancer Centre in Northern India

Blood ◽

10.1182/blood.v112.11.4290.4290 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4290-4290

Author(s):

Vineet Talwar ◽

Dinesh Bhurani ◽

Dinesh Chandra Doval ◽

Ajay Kumar Sharma

Keyword(s):

Adverse Events ◽

Median Duration ◽

Blast Crisis ◽

Chronic Phase ◽

Cytogenetic Response ◽

Imatinib Therapy ◽

Toxicity Profile ◽

Imatinib Resistance ◽

Hematologic Response ◽

Favorable Toxicity Profile

Abstract INTRODUCTION: Dasatinib is a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases. It is structurally unrelated to imatinib, binding to the oncologically relevant catalytically active conformation of BCR ABL. It is active against all tested BCR ABL mutations except T315I that confer Imatinib resistance. AIM: Primary Aim: Survival with Dasatinib. Secondary Aim: Toxicity profile of Dasatinib. MATERIALS AND METHODS: A total number of 12 patients were included in this study with a median age of 40 years. Five patients were male and seven female. The median duration, since starting therapy for CML was 58.9 months. The median duration since start of treatment with dasatinib was 9.5 months. Out of the 12 patients, 9 were in chronic phase (75%) and 3 were in myeloid blast crisis (25%). Amongst these, 8 patients (66.7%) had taken prior imatinib therapy for more than 3 years. The dose of prior imatinib therapy ranged from 400 mg in patients of chronic phase to upto 800mg in blast crisis patients. For inclusion in the study, patients were required to have adequate hepatic and renal function and eastern co-operative oncology group (ECOG) performance score of 2 or lower. Exclusion criteria included previous dasatinib therapy, significant cardiovascular disease or significant bleeding disorder unrelated to CML. Imatinib failure was defined as progression from chronic phase to blast crisis while receiving 400mg/day or more imatinib or from accelerated phase to blast crisis while receiving 600mg/day or more imatinib. The hematology and cytogenetic responses were accessed as per standard criteria. RESULTS: A total number of 12 patients were enrolled in this pilot study out of which 7 are still on therapy. 5 patients discontinued therapy due to death. The median duration of dasatinib therapy was 7.5 months. The longest follow up patient on therapy being 20 months. The median daily dasatinib dose was 100mg. Nine patients (75%) had a major hematologic response and three patients (25%) had minor hematologic response. Dasatinib induced a major cytogenetic response in 5 (41.7%) patients, minor cytogenetic response in 1 (8.5%) patients, and minimal cytogenetic response in 4 (33.3%) patients. No cytogenetic response was seen in 2 patients of blast crisis. The median duration of survival was not achieved till August 2008. The one year survival by Kaplan-Meier method is 64% (1 month – 19 months). Dasatinib had a favorable toxicity profile. Among the non hematologic events, the most frequent adverse events were diarrhea (3/12), vomiting (3/12), peripheral edema (4/12), arthralgia (3/12), fatigue (5/12), rash (3/12), epistaxis (2/12), fever (1/12) and headache (2/12). Dose interruption was required for one patient with pleural effusion which was reversible with diuretics and steroids. No patients had grade 4 toxicity. The cytopenias were generally reversible and could be managed effectively by dose interruption or reduction. Since these patients had prior therapy with imatinib, assessment of relative contribution of therapy to myelosuppression could be a confounding factor. CONCLUSION: Dasatinib induced hematologic and cytogenetic response in majority of patients who had progressed on imatinib therapy. Dasatinib has a favorable toxicity profile. The hematologic and non hematologic adverse events could be managed with dose alterations. It presents a potentially new therapeutic option for patients with imatinib failure or intolerance.

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