An Overview of the Optimal Planning, Design, and Conduct of Phase I Studies of New Therapeutics

LoRusso, Patricia; Boerner, Scott A.; Seymour, Lesley

doi:10.1158/1078-0432.ccr-09-1993

Cited by 85 publications

(78 citation statements)

References 40 publications

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“…Answer: The goal of this study was to evaluate, whether the addition of cytotoxic agents to the standard treatment of adult medulloblastoma is feasible without unacceptable toxicity in a prespecified number of patients according to published literature 1 . This hypothesis results in an exploratory and descriptive feasibility design, focusing on the rate of toxicity-related treatment terminations after 4 cycles of adjuvant chemotherapy.…”

Section: "However a Crucial Point Remains Since Authors Did Not Ansmentioning

confidence: 99%

Multicenter pilot study of radiochemotherapy as first-line treatment for adults with medulloblastoma (NOA-07)

et al. 2017

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Abstract:Background: Medulloblastoma in adult patients is rare, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. No prospective data on the feasibility of radio-chemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective descriptive multicenter single-arm Phase II trial to evaluate feasibility and toxicity of radio-polychemotherapy. Methods: The NOA-07 trial combined cranio-spinal irradiation with vincristine, followed by eight cycles of cisplatin, lomustine and vincristine. Adverse events, imaging and progression patterns, histological and genetic markers, health-related quality of life (HRQoL) and cognition were evaluated. Primary endpoint was the rate of toxicityrelated treatment terminations after four chemotherapy cycles, and the toxicity profile. The feasibility goal was reached if at least 45% of patients received at least 4 cycles of maintenance chemotherapy. Results: Thirty patients were evaluable. Each 50% percent showed classic and desmoplastic-nodular histology. Sixty-seven percent were classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13% in wingless (WNT), and 17% in Non-WNT/Non-SHH. Four cycles of chemotherapy were feasible in the majority (n=21; 70.0%). Hematological side effects and polyneuropathy were prevalent toxicities. During the active treatment period, HRQoL and verbal fluency improved significantly. The 3-year event-free survival rate (EFS) was 66.6% at the time of databank lock. Conclusions: Radio-polychemotherapy did lead to considerable toxicity and a high amount of dose reductions throughout the first four chemotherapy cycles that may affect efficacy. Thus, we propose frequent patient surveillance using this regimen.Modifications of the regimen may increase feasibility of radio-polychemotherapy of adult patients with medulloblastoma. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation N-O-D-17-00180R1Dear Prof. Wen, many thanks for the opportunity to, for the second time, re-submit our above mentioned manuscript to NeuroOncology with major revisions.Below, you will find our point-to-point answer to all reviewer comments. Please be aware that there are two open questions where we will need the feedback of the acting editor and the reviewer, respectively.We declare that our manuscript, or any part of it, has not been previously published or submitted concurrently to any other journal, and that all co-authors have read and approved the revised version of the manuscript. We further declare that we agree to pay for full color reproduction.We hope that the revisions will now qualify the manuscript for publication in Neuro-Oncology. We will however be happy to address further questions, if indicated. . This hypothesis results in an exploratory and descriptive feasibility design, focusing on the rate of toxicity-related treatment terminations after 4 cycles of adjuvant chemotherapy. The statistical approach of this study therefore did not contain a formal H0/...

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Section: "However a Crucial Point Remains Since Authors Did Not Ansmentioning

confidence: 99%

Multicenter pilot study of radiochemotherapy as first-line treatment for adults with medulloblastoma (NOA-07)

et al. 2017

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“…Synergistic treatment effects may be achieved using 2 agents that target similar cellular pathways. Rational combination strategies that target different cellular pathways simultaneously may circumvent possible bypass mechanisms that contribute to drug resistance and treatment failure (14,15). Combination therapies may also overcome the tumor-to-tumor and intratumor heterogeneity of cancer cells within individual patients, particularly in advanced disease where the genetic instability of tumor cells fosters the emergence of multiple metastatic clones, each with a different genetic profile and varying sensitivity to specific treatments (16)(17)(18)(19).…”

Section: Why Combinations Are Necessarymentioning

confidence: 99%

Accelerating Cancer Therapy Development: The Importance of Combination Strategies and Collaboration. Summary of an Institute of Medicine Workshop

LoRusso

Canetta

Wagner

et al. 2012

Clinical Cancer Research

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Cancer cells contain multiple genetic changes in cell signaling pathways that drive abnormal cell survival, proliferation, invasion, and metastasis. Unfortunately, patients treated with single agents inhibiting only one of these pathways-even if showing an initial response-often develop resistance with subsequent relapse or progression of their cancer, typically via the activation of an alternative uninhibited pathway. Combination therapies offer the potential for inhibiting multiple targets and pathways simultaneously to more effectively kill cancer cells and prevent or delay the emergence of drug resistance. However, there are many unique challenges to developing combination therapies, including devising and applying appropriate preclinical tests and clinical trial designs, prioritizing which combination therapies to test, avoiding overlapping toxicity of multiple agents, and overcoming legal, cultural, and regulatory barriers that impede collaboration among multiple companies, organizations, and/or institutions. More effective strategies to efficiently develop combination cancer therapies are urgently needed. Thus, the Institute of Medicine's National Cancer Policy Forum recently convened a workshop with the goal of identifying barriers that may be impeding the development of combination investigational cancer therapies, as well as potential solutions to overcome those barriers, improve collaboration, and ultimately accelerate the development of promising combinations of investigational cancer therapies.

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“…1. The study was designed as 3 þ 3 dose escalation clinical trial (23,24). Panitumumab was administered weekly for 6 weeks by intravenous infusion in different dose levels per cohort (1, 1.5, 2, and 2.5 mg/kg) during gemcitabine-based CRT.…”

Section: Study Treatmentmentioning

confidence: 99%

Phase I Clinical Trial to Determine the Feasibility and Maximum Tolerated Dose of Panitumumab to Standard Gemcitabine-Based Chemoradiation in Locally Advanced Pancreatic Cancer

Zweeden

Vliet

Wilmink

et al. 2015

Clinical Cancer Research

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Purpose: Epidermal growth factor receptor (EGFR) inhibitors may improve both the therapeutic efficacy of radiotherapy and the radiosensitizing activity of gemcitabine. Based on this rationale and the nonoverlapping toxicity profiles of gemcitabine and the monoclonal EGFR antibody panitumumab, we designed a phase I trial to investigate the maximum-tolerated dose (MTD), safety, and activity of panitumumab added to gemcitabine-based chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer (LAPC).Experimental Design: Patients with LAPC and WHO performance status 0 to 1 were treated with weekly panitumumab at four dose levels (1-2.5 mg/kg), combined with weekly gemcitabine 300 mg/m 2 and radiotherapy (50.4 Gy in 28 fractions) for 6 weeks, followed by gemcitabine 1,000 mg/m 2 weekly for 3 weeks every 4 weeks until disease progression or unacceptable toxicity.Each cohort was monitored during the combination therapy to establish dose limiting toxicity. Tumor evaluation was performed after CRT and during gemcitabine monotherapy.Results: Fourteen patients were enrolled; 14 were evaluable for toxicity and 13 for response. The MTD for panitumumab was 1.5 mg/kg.

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An Overview of the Optimal Planning, Design, and Conduct of Phase I Studies of New Therapeutics

Cited by 85 publications

References 40 publications

Multicenter pilot study of radiochemotherapy as first-line treatment for adults with medulloblastoma (NOA-07)

Multicenter pilot study of radiochemotherapy as first-line treatment for adults with medulloblastoma (NOA-07)

Accelerating Cancer Therapy Development: The Importance of Combination Strategies and Collaboration. Summary of an Institute of Medicine Workshop

Phase I Clinical Trial to Determine the Feasibility and Maximum Tolerated Dose of Panitumumab to Standard Gemcitabine-Based Chemoradiation in Locally Advanced Pancreatic Cancer

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