Outcomes of Patients with Metastatic Melanoma Treated with Molecularly Targeted Agents in Phase I Clinical Trials

Oncology ◽  
2011 ◽  
Vol 81 (2) ◽  
pp. 135-140 ◽  
Author(s):  
Montserrat Blanco Codesido ◽  
Andre Tesainer Brunetto ◽  
Sophia Frentzas ◽  
Victor Moreno Garcia ◽  
Dionysis Papadatos-Pastos ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Metastatic Melanoma ◽  
Targeted Agents ◽  
Phase I Clinical Trials ◽  
Molecularly Targeted Agents

Targeted agents matched with tumor molecular aberrations: Review of 160 patients with advanced melanoma treated in a phase I clinic.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8551-8551
Author(s):  
Haby Adel Henary ◽  
David S. Hong ◽  
Gerald Steven Falchook ◽  
Apostolia Maria Tsimberidou ◽  
Goldy George ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Systemic Therapy ◽  
Phase I Trial ◽  
Phase 1 ◽  
Targeted Agents ◽  
Phase I Clinical Trials ◽  
Kit Mutation ◽  
Targeted Agent ◽  
Molecular Aberrations

8551 Background: Identification of activating mutations in melanoma has increased the number of novel targeted agents for this disease. Methods: Weretrospectively reviewed clinical outcomes of 160 consecutive metastatic melanoma patients (pts) treated in the Dept of Investigational Cancer Therapeutics (Phase I program) at M. D. Anderson since 2008, and compared their median progression free survival (PFS) to their first and last standard systemic therapy PFS. In addition, we compared those pts’ outcomes tested for tumor molecular aberrations on a phase I trial with a matched targeted agent with those of pts who were treated without regard for their molecular profiles. Results: Of 160 pts treated on 35 different phase 1 clinical trials, 110 pts (69%) had ≥ 1 molecular aberration. Of those pts who had adequate tissue for molecular analysis, 63% (85/134) pts had BRAF mutation, 20% (22/109) NRAS mutation, 20% (1/5) GNAQ mutation, 11% (1/9) P53 mutation, 2.5% (1/39) PIK3CA and 1.3% (1/76) had KIT mutation. 77 (48%) pts were treated on a phase I trial with a matched targeted agent and 83 (52%) pts were treated on a non-matched phase 1 trial. The overall response rate was 39% (complete response [CR], 9%; partial response [PR], 30%) in the 77 pts treated with matched therapy and 9% (all PRs) in the 83 pts treated without matched therapy (P = 0.0018). 139 (87%) pts received at least one systemic therapy before referral to phase I, median PFS was longer on phase 1 therapy than on last line standard therapy prior to referral to phase 1 (4.2 vs. 2.8 months, P = 0.002). Median PFS was greater for pts on matched vs. non-matched therapy (5.3 vs. 3.7 months, log rank P = 0.004). Also, median PFS was longer on phase 1 matched trial than on first standard treatment (5.3 vs. 3.9 months, log rank P = 0.045).PFS did not differ between first standard and non-matched phase 1 study. Univariate analyses with the log rank test revealed that matched therapy (P = 0.004) was positively associated with longer PFS on phase I clinical trials. Conclusions: Matching melanoma pts with targeted drugsbased on specific molecular aberrations in the phase I setting can be associated with superior outcomes compared to prior standard systemic therapies.

scholarly journals Phase I/II dose-finding design for molecularly targeted agent: Plateau determination using adaptive randomization

2016 ◽  
Vol 27 (2) ◽  
pp. 466-479 ◽  
Author(s):  
Marie-Karelle Riviere ◽  
Ying Yuan ◽  
Jacques-Henri Jourdan ◽  
Frédéric Dubois ◽  
Sarah Zohar
Keyword(s):  
Phase I ◽  
Late Onset ◽  
Optimal Dose ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Targeted Agents ◽  
Weighted Likelihood ◽  
Operating Characteristics ◽  
Phase I Clinical Trials ◽  
Molecularly Targeted Agents

Conventionally, phase I dose-finding trials aim to determine the maximum tolerated dose of a new drug under the assumption that both toxicity and efficacy monotonically increase with the dose. This paradigm, however, is not suitable for some molecularly targeted agents, such as monoclonal antibodies, for which efficacy often increases initially with the dose and then plateaus. For molecularly targeted agents, the goal is to find the optimal dose, defined as the lowest safe dose that achieves the highest efficacy. We develop a Bayesian phase I/II dose-finding design to find the optimal dose. We employ a logistic model with a plateau parameter to capture the increasing-then-plateau feature of the dose–efficacy relationship. We take the weighted likelihood approach to accommodate for the case where efficacy is possibly late-onset. Based on observed data, we continuously update the posterior estimates of toxicity and efficacy probabilities and adaptively assign patients to the optimal dose. The simulation studies show that the proposed design has good operating characteristics. This method is going to be applied in more than two phase I clinical trials as no other method is available for this specific setting. We also provide an R package dfmta that can be downloaded from CRAN website.

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