Reaffirming and Clarifying the American Society of Clinical Oncology’s Policy Statement on the Critical Role of Phase I Trials in Cancer Research and Treatment
“…Phase 1 trials are important for the development of novel agents for cancers. The American Society of Clinical Oncology (ASCO) policy statement emphasised the therapeutic role of phase 1 trials in cancer (Weber et al, 2017). As with our cohort, ASCO commented that many patients enrolled onto these trials go on to have further therapy, challenging the paradigm that phase 1 trials are offered to patients with no other options except palliation.…”
Section: Clinical Outcomes and Survival Of Patients With Myeloma And mentioning
Karenko, L., Kahkonen, M., Hyytinen, E.R., Lindlof, M. & Ranki, A. (1999) Notable losses at specific regions of chromosomes 10q and 13q in the Sezary syndrome detected by comparative genomic hybridization.
“…Phase 1 trials are important for the development of novel agents for cancers. The American Society of Clinical Oncology (ASCO) policy statement emphasised the therapeutic role of phase 1 trials in cancer (Weber et al, 2017). As with our cohort, ASCO commented that many patients enrolled onto these trials go on to have further therapy, challenging the paradigm that phase 1 trials are offered to patients with no other options except palliation.…”
Section: Clinical Outcomes and Survival Of Patients With Myeloma And mentioning
Karenko, L., Kahkonen, M., Hyytinen, E.R., Lindlof, M. & Ranki, A. (1999) Notable losses at specific regions of chromosomes 10q and 13q in the Sezary syndrome detected by comparative genomic hybridization.
“…Furthermore, tumors with high mutational burden are more likely to harbor neoantigens and the presence of neoantigens is correlated with improved response to immunotherapies, such as antibodies against CTLA-4 and PD-L1, that reactivate the immune system (see for example [111–113]). Although cancer immunotherapy shows great promise, there are several adverse events associated with this type of therapy, and several of them are associated with autoimmunity (for reviews see [114, 115]).…”
Section: Mechanisms Associated With Defective Dna Repair and Slementioning
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with no known cure that affects at least five million people worldwide. Monozygotic twin concordance and familial aggregation studies strongly suggest that lupus results from genetic predisposition along with environmental exposures including UV light. The majority of the common risk alleles associated with genetic predisposition to SLE map to genes associated with the immune system. However, evidence is emerging that implicates a role for aberrant DNA repair in the development of lupus. Here we summarize our current knowledge of the potential association of lupus with mutations in DNA repair genes. We also discuss how defective or aberrant DNA repair could lead to the development of lupus.
“…Although not always predictive of survival benefit, ORRs are deemed by the U.S. Food and Drug Administration (FDA) to be the outcomes most attributable to the intervention under evaluation in a single‐arm study. Measures such as survival, progression‐free survival, and time to progression are not adequately characterized in single‐arm studies and not recommended as end points for phase I trials 9 . In accordance with the FDA Safety and Innovation Act, the FDA is permitted to use the durable objective response as one of the criterion for accelerated approval of new drugs, and there are recent examples of If slightly greater risks are accepted and adaptive trial designs are enacted, phase I participants can have an increased chance of therapeutic benefit.…”
Section: The Merits Of Minimizing Risk In Phase I Studiesmentioning
The scientific purpose of phase I trials is to determine the maximum tolerated dose and/or optimal biological dose of experimental agents. Yet most participants in phase I oncology trials enroll hoping for direct medical benefit. The most common phase I trial designs use low starting doses and escalate cautiously in a “risk‐escalation” model focused on minimizing risk for each participant. This approach ensures that a proportion of subjects will likely not receive any benefit, even if the intervention proves to be successful at appropriate doses. In this article, we propose that trial designs should employ dosing strategies that increase chances of providing benefit if the investigational agent should prove to be successful while limiting risk to reasonable levels. We then describe how adaptive trial designs can facilitate refined dose optimization based on both therapeutic benefit and toxicity, which can simultaneously decrease the risk of harm while increasing the chances of benefit.
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