Potential utility of a longitudinal relative dose intensity of molecularly targeted agents in phase 1 dose‐finding trials

Hirakawa, Akihiro; Yonemori, Kan; Kinoshita, Fumie; Kobayashi, Yumiko; Okuma, Hitomi Sumiyoshi; Kawachi, Asuka; Tamura, Kenji; Fujiwara, Yasuhiro; Rubinstein, Larry; Harris, Pamela Jo; Takebe, Naoko

doi:10.1111/cas.13436

Cited by 7 publications

(8 citation statements)

References 28 publications

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“…There is growing emphasis on the need to take into account repetitive grade 2 toxicity events observed during continuous dosing in the definition of dose-limiting toxicity (DLT). [12][13][14][15] Information throughout the treatment cycles, specifically about intolerable clinical grade 2 toxicities leading to a reduction in patients' relative dose intensity, should be incorporated when the recommended phase 2 dose is determined for further studies. 15 The low-grade AEs observed in this study, particularly those attributable to the investigated agent during treatment, seem to be more prevalent in women with gynecologic cancers and may not be recognized as problematic.…”

Section: Discussionmentioning

confidence: 99%

“…The majority of gynecologic cancers were ovarian/fallopian tube/peritoneal cancers (n = 527 [77%]), which were followed by cervical cancer (n = 76 [11%]) and uterine cancer (n = 72 [11%]). The median number of lines of treatment before study enrollment for all patients was 4 (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”

Section: Patient Characteristicsmentioning

confidence: 99%

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Evaluation of toxicities related to novel therapy in clinical trials for women with gynecologic cancer

Lee

Wang

Kohn

et al. 2020

Cancer

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BACKGROUND: Women with gynecologic cancer may be at increased risk for adverse events (AEs) due to peritoneal disease burden and prior treatment (surgery, chemotherapy, and pelvic radiotherapy). This study compared the toxicity profiles of patients with and without gynecologic cancer enrolled in phase 1 trials. METHODS: This was a retrospective analysis of the National Cancer Institute phase 1 database for all trials enrolling 1 or more patients with gynecologic cancer over 2 decades . Clinical parameters collected included demographics, cancer history, trial information, AEs, and responses. AEs (according to the Common Terminology Criteria for Adverse Events) were documented for each patient during treatment, and they were counted once and analyzed on the basis of the highest grade and drug attribution. Multiple regression models were used to compare AEs at the baseline and during treatment. RESULTS: A total of 4269 patients enrolled in 150 trials were divided into 3 groups: 1) women with gynecologic cancer (n = 685), 2) women with nongynecologic cancer (n = 1698), and 3) men with cancer (n = 1886). The median age was 58 years. The mean number of total AEs reported during treatment was highest for women with gynecologic cancer (17.1 vs 14.7 vs 13.5; P < .001), even though they were similar at the baseline (7.0 vs 7.4 vs 7.0; P = .09). The mean number of drug-related AEs was also highest for women with gynecologic cancer (8.3 vs 6.9 vs 6.2; P < .001). Grade 3 to 5 AEs were similar (2.3 vs 2.3 vs 2.1); however, grade 2 AEs were more frequent in women with gynecologic cancer (4.6 vs 3.9 vs 3.5). Treatment discontinuations due to AEs were similar (9% vs 9% vs 10%). CONCLUSIONS: Women with gynecologic cancer experienced more frequent low-grade AEs during treatment, and this warrants attention to support their symptom burden. Study dose management should be considered for recurrent grade 2 AEs, particularly during continuous therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Patient Characteristicsmentioning

confidence: 99%

Evaluation of toxicities related to novel therapy in clinical trials for women with gynecologic cancer

Lee

Wang

Kohn

et al. 2020

Cancer

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“…Investigators, however, feel that such an RP2D may not be “optimal” for MTA clinical use due to late-onset and/or cumulative toxicity [[10], [11], [12]]. Additionally, some patients develop chronic low-grade toxicity from MTAs during the phase 1 trial period.…”

Section: Introductionmentioning

confidence: 99%

Pragmatic dose-escalation methods incorporating relative dose intensity assessment for molecularly targeted agents in phase I trials

Hirakawa

Tanaka

Kaneko

2019

Contemporary Clinical Trials Communications

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The recommended phase 2 doses of molecularly targeted agents, determined by using an ordinal dose-finding method that only uses toxicity data at first cycle, may not be optimal. Some researchers have proposed the use of relative dose intensity that can account for late-onset, cumulative, and low-grade toxicities to determine the recommended phase 2 dose (RP2D). In this study, we proposed two dose escalation methods based on the observed relative dose intensities (RDIs) between the pre-specified intervals (cycles) for toxicity evaluation used in combination with DLT evaluation in the first cycle. First, we propose the modified 3 + 3 design that incorporates longitudinal RDI assessment. Second, we propose the sequential assessment method for longitudinal RDI (SARDI) to achieve faster dose escalation compared to that of the modified 3 + 3 design. Simulation studies demonstrated that the SARDI was, in many cases, superior to the ordinal and modified 3 + 3 designs in respect to the selection rate of true RP2D and study period. The two proposed methods could also in some cases decrease the average number of patients enrolled in the trial compared to that of the ordinary 3 + 3 design. Incorporation of the RDI assessment into the 3 + 3 design is not difficult and does not require the use of complex statistical techniques. Therefore, we believe that investigators who routinely use the 3 + 3 design in practice can easily use our proposed methods.

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“…However, molecularly targeted agents (MTAs) often show late‐onset, chronic low‐grade toxicities over time or different longitudinal toxicity profiles from those of CDs . These toxicities eventually become intolerable and can be a major factor that leads to dose reduction or interruption, and result in insufficient drug exposure . The characterization and understanding of the longitudinal toxicity profile of cancer drug treatments may be important in determining the RP2D and to manage drug‐related adverse reactions in clinical practice.…”

mentioning

confidence: 99%

“…[8][9][10][11][12][13][14][15] These toxicities eventually become intolerable and can be a major factor that leads to dose reduction or interruption, and result in insufficient drug exposure. 16 The characterization and understanding of the longitudinal toxicity profile of cancer drug treatments may be important in determining the RP2D and to manage drug-related adverse reactions in clinical practice.…”

mentioning

confidence: 99%

A Comparative Study of Longitudinal Toxicities of Cytotoxic Drugs, Molecularly Targeted Agents, Immunomodulatory Drugs, and Cancer Vaccines

Hirakawa

Sudo²,

Yonemori

et al. 2019

Clin Pharma and Therapeutics

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Little is known about the toxicity of various therapeutics for cancer over time because randomized controlled clinical trials that compare several treatments are limited. In this study, we focused on the toxicities most frequently discussed, which are investigations (lab abnormalities), gastrointestinal disorders, skin and subcutaneous tissue disorders, and cardiac disorders, and compared their longitudinal toxicity data among four types of cancer therapeutics. In total, 28,235 patients who were enrolled into 772 early‐phase trials to evaluate the monotherapies of cytotoxic drugs, molecularly targeted agents, immunomodulatory drugs, or cancer vaccines were evaluated. For each toxicity, we compared their grade prevalence, mean grade at each cycle, and time to toxicity occurrence and identified the potential underlying similarities and differences of longitudinal toxicities among the four cancer treatment types. Our results will further help in understanding the profile of cancer therapeutic toxicities and their impact on oncology treatment in practice.

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Potential utility of a longitudinal relative dose intensity of molecularly targeted agents in phase 1 dose‐finding trials

Cited by 7 publications

References 28 publications

Evaluation of toxicities related to novel therapy in clinical trials for women with gynecologic cancer

Evaluation of toxicities related to novel therapy in clinical trials for women with gynecologic cancer

Pragmatic dose-escalation methods incorporating relative dose intensity assessment for molecularly targeted agents in phase I trials

A Comparative Study of Longitudinal Toxicities of Cytotoxic Drugs, Molecularly Targeted Agents, Immunomodulatory Drugs, and Cancer Vaccines

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