Unified approach for extrapolation and bridging of adult information in early-phase dose-finding paediatric studies

The number of trials conducted and the number of patients per trial are typically small in paediatric clinical studies. This is due to ethical constraints and the complexity of the medical process for treating children. While incorporating prior knowledge from adults may be extremely valuable, this must be done carefully. In this paper, we propose a unified method for designing and analysing dose-finding trials in paediatrics, while bridging information from adults. The dose-range is calculated under three extrapolation options, linear, allometry and maturation adjustment, using adult pharmacokinetic data. To do this, it is assumed that target exposures are the same in both populations. The working model and prior distribution parameters of the dose–toxicity and dose–efficacy relationships are obtained using early-phase adult toxicity and efficacy data at several dose levels. Priors are integrated into the dose-finding process through Bayesian model selection or adaptive priors. This calibrates the model to adjust for misspecification, if the adult and pediatric data are very different. We performed a simulation study which indicates that incorporating prior adult information in this way may improve dose selection in children.

Download Full-text

Tg.rasH2 Mice and not CByB6F1 Mice Should Be Used for 28-Day Dose Range Finding Studies Prior to 26-Week Tg.rasH2 Carcinogenicity Studies

International Journal of Toxicology ◽

10.1177/1091581817707458 ◽

2017 ◽

Vol 36 (4) ◽

pp. 287-292 ◽

Cited By ~ 1

Author(s):

Madhav G. Paranjpe ◽

Jessica Belich ◽

Tom J. Vidmar ◽

Reem H. Elbekai ◽

Marie McKeon ◽

...

Keyword(s):

Selection Process ◽

Dose Range ◽

Maximum Tolerated Dose ◽

High Dose ◽

Dose Selection ◽

Range Finding ◽

Body Weights ◽

Vehicle Test ◽

High Doses ◽

Dose Levels

Our recent retrospective analysis of data, collected from 29 Tg.rasH2 mouse carcinogenicity studies, determined how successful the strategy of choosing the high dose for the 26-week studies was based on the estimated maximum tolerated dose (EMTD) derived from earlier 28-day dose range finding (DRF) studies conducted in CByB6F1 mice. Our analysis demonstrated that the high doses applied at EMTD in the 26-week Tg.rasH2 studies failed to detect carcinogenic effects. To investigate why the dose selection process failed in the 26-week carcinogenicity studies, the initial body weights, terminal body weights, body weight gains, food consumption, and mortality from the first 4 weeks of 26-week studies with Tg.rasH2 mice were compared with 28-day DRF studies conducted with CByB6F1 mice. Both the 26-week and the earlier respective 28-day studies were conducted with the exact same vehicle, test article, and similar dose levels. The analysis of our results further emphasizes that the EMTD and subsequent lower doses, determined on the basis of the 28-day studies in CByB6F1 mice, may not be an accurate strategy for selecting appropriate dose levels for the 26-week carcinogenicity studies in Tg.rasH2 mice. Based on the analysis presented in this article, we propose that the Tg.rasH2 mice and not the CByB6F1 mice should be used in future DRF studies. The Tg.rasH2 mice demonstrate more toxicity than the CByB6F1 mice, possibly because of their smaller size compared to CByB6F1 mice. Also, the Tg.rasH2 males appear to be more sensitive than the female Tg.rasH2 mice.

Download Full-text

Pharmacodynamic-guided, modified continuous reassessment method (mCRM)-based, dose finding study of rapamycin in adult patients with solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3020 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 3020-3020 ◽

Cited By ~ 1

Author(s):

A. Jimeno ◽

P. Kulesza ◽

G. Cusatis ◽

A. Howard ◽

Y. Khan ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Level ◽

Dose Escalation ◽

Dose Finding ◽

Phase I Trials ◽

Dose Selection ◽

Normal Tissues ◽

Tumor Biopsies ◽

Dose Levels

3020 Background: Pharmacodynamic (PD) studies, using either surrogate or tumor tissues, are frequently incorporated in Phase I trials. However, it has been less common to base dose selection, the primary endpoint in Phase I trials, in PD effects. We conducted a PD-based dose selection study with rapamycin (Rap). Methods: We used the modified continuous reassessment method (mCRM), a computer-based dose escalation algorithm, and adapted the logit function from its classic toxicity-based input data to a PD-based input. We coupled this design to a Phase I trial of Rap with 2 parts: a dose estimation phase where PD endpoints are measured in normal tissues and a confirmation phase where tumor tissue is assessed. Patients (pts) had solid tumors refractory to standard therapy. Rap was given starting at 2 mg/day continuously in 3-pt cohorts. The PD endpoint was pP70S6K in skin and tumor. Biopsies were done on days 0 and 28 of cycle 1, and a PD effect was defined as ≥ 80% inhibition from baseline. The first 2 dose levels (2 and 3 mgs) were evaluated before implementing the mCRM. The data was then fed to the computer that based on the PD effect calculated the next dose level. The mCRM was set so escalation continued until a dose level elicited a PD effect and the mCRM assigned the same dose to 8 consecutive pts, at which point the effect of that dose will be confirmed in tumor biopsies. Other correlates were PET-CT and pharmacokinetics. Results: Ten pts were enrolled at doses of 2 mg (n = 4), 3 mg (n = 3) and 6 mg (n = 3). Toxicity was anemia (4 G1, 1 G2), leucopenia (1 G1, 2 G2), low ANC (2 G2), hyperglycemia (2 G1, 1 G2), hyperlipidemia (4 G1), and mucositis (1 G1, 1 G2). PD responses were seen in 2 and 1 pt at 2 and 3 mg dose levels. Input of data to the mCRM selected a dose of 6 mg for the third cohort, where PD effect was seen in 1 pt, and thus a fourth dose around 9 mg will be tested. No responses by RECIST occurred, but 2 pts had a response by PET. The PK was consistent with prior data (t1/2 24.6 ± 10.2 h, CL 31.4 ± 12.0 L/h, vol of distribution 235 ± 65 L), and exposure increased with dose. Steady-state concentration were in the 5–20 nM range. Conclusions: mCRM-based dose escalation based on real-time PD assessment is feasible and permits the exploitation of PD effects for dose selection in a rational manner. No significant financial relationships to disclose.

Download Full-text

Pharmacodynamic-Guided Modified Continuous Reassessment Method–Based, Dose-Finding Study of Rapamycin in Adult Patients With Solid Tumors

Journal of Clinical Oncology ◽

10.1200/jco.2008.16.2347 ◽

2008 ◽

Vol 26 (25) ◽

pp. 4172-4179 ◽

Cited By ~ 41

Author(s):

Antonio Jimeno ◽

Michelle A. Rudek ◽

Peter Kulesza ◽

Wen Wee Ma ◽

Jenna Wheelhouse ◽

...

Keyword(s):

Real Time ◽

Solid Tumors ◽

Mononuclear Cells ◽

Maximum Tolerated Dose ◽

Dose Finding ◽

Pharmacodynamic Effect ◽

Dose Selection ◽

Peripheral Blood Mononuclear ◽

End Point ◽

Dose Levels

Purpose Pharmacodynamic studies are frequently incorporated into phase I trials, but it is uncommon that they guide dose selection. We conducted a dose selection study with daily rapamycin (sirolimus) in patients with solid tumors employing a modified continuous reassessment method (mCRM) using real-time pharmacodynamic data as primary dose-estimation parameter. Patients and Methods We adapted the mCRM logit function from its classic toxicity-based input data to a pharmacodynamic-based input. The pharmacodynamic end point was skin phospho-P70 change after 28 days. Pharmacodynamic effect was defined as at least 80% inhibition from baseline. The first two dose levels (2 and 3 mg) were evaluated before implementing the mCRM, and the data used to estimate the next dose level based on statistical modeling. Toxicity-based boundaries limited the escalation steps. Other correlates analyzed were positron emission tomography (PET) and computed tomography, pharmacokinetics, phospho-P70 in peripheral-blood mononuclear cells, and tumor biopsies in patients at the maximum-tolerated dose (MTD). Results Twenty-one patients were enrolled at doses between 2 and 9 mg. Pharmacodynamic effect occurred across dose levels, and toxicity boundaries ultimately drove dose selection. The MTD of daily oral rapamycin was 6 mg. Toxicities in at least 20% were hyperglycemia, hyperlipidemia, elevated transaminases, anemia, leucopenia, neutropenia, and mucositis. Pharmacokinetics were consistent with prior data, and exposure increased with dose. No objective responses occurred, but five previously progressing patients received at least 12 cycles. PET showed generalized stable or decreased glucose uptake unrelated to antitumor effect. Conclusion mCRM-based dose escalation using real-time pharmacodynamic assessment was feasible. However, the selected pharmacodynamic end point did not correlate with dose. Toxicity ultimately drove dose selection. Rapamycin is a well-tolerated and active oral anticancer agent.

Download Full-text

Competitive blocking of salivary gland [18F]DCFPyL uptake via localized, retrograde ductal injection of non-radioactive DCFPyL: a preclinical study

EJNMMI Research ◽

10.1186/s13550-021-00803-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jyoti Roy ◽

Blake M. Warner ◽

Falguni Basuli ◽

Xiang Zhang ◽

Changyu Zheng ◽

...

Keyword(s):

Salivary Gland ◽

Dose Range ◽

Systemic Circulation ◽

Preclinical Study ◽

Dose Finding ◽

Tumor Uptake ◽

Tumor Bearing ◽

Biodistribution Studies ◽

Novel Approach ◽

Dose Levels

Abstract Background PSMA-targeted radionuclide therapy (TRT) is a promising treatment for prostate cancer (PCa), but dose-limiting xerostomia can severely limit its clinical adaptation, especially when using alpha-emitting radionuclides. With [18F]DCFPyL as a surrogate for PSMA-TRT, we report a novel method to selectively reduce salivary gland (SG) uptake of systemically administered [18F]DCFPyL by immediate prior infusion of non-radioactive standard of [18F]DCFPyL (DCFPyL) directly into the SG via retrograde cannulation. Methods A dose-finding cohort using athymic nude mice demonstrated proof of principle that SG uptake can be selectively blocked by DCFPyL administered either locally via cannulation (CAN group) or systemically (SYS group). The experiments were repeated in a validation cohort of 22RV1 tumor-bearing mice. Submandibular glands (SMG) of CAN mice were locally blocked with either saline or DCFPyL (dose range: 0.01× to 1000× molar equivalent of the radioactive [18F]DCFPyL dose). The radioactive dose of [18F]DCFPyL was administered systemically 10 min later and the mice euthanized after 1 h for biodistribution studies. Toxicity studies were done at up to 1000× dose. Results In the dose-finding cohort, the SYS group showed a dose-dependent 12–40% decrease in both the SMG T/B and the kidney (tumor surrogate). Mild blocking was observed at 0.01× , with maximal blocking reached at 1× with no additional blocking up to 1000× . In the CAN group, blocking at the 0.1× and 1× dose levels resulted in a similar 42–53% decrease, but without the corresponding decrease in kidney uptake as seen in the SYS group. Some evidence of “leakage” of DCFPyL from the salivary gland into the systemic circulation was observed. However, experiments in 22RV1 tumor-bearing mice at the 0.1× and 1× dose levels confirm that, at the appropriate blocking dose, SG uptake of [18F]DCFPyL can be selectively reduced without affecting tumor uptake and with no toxicity. Conclusion Our results suggest that direct retrograde instillation of DCFPyL into the SG could predictably and selectively decrease salivary uptake of systemically administered [18F]DCFPyL without altering tumor uptake, if given at the appropriate dose. This novel approach is easily translatable to clinical practice and has the potential to mitigate xerostomia, without compromising the therapeutic efficacy of the PSMA-TRT.

Download Full-text

Competitive Blocking of Salivary Gland [18F]DCFPyL Uptake via Localized, Retrograde Ductal Injection of Non-radioactive DCFPyL: A Preclinical Study

10.21203/rs.3.rs-428523/v1 ◽

2021 ◽

Author(s):

Jyoti Roy ◽

Blake M Warner ◽

Falguni Basuli ◽

Xiang Zhang ◽

Changyu Zheng ◽

...

Keyword(s):

Salivary Gland ◽

Dose Range ◽

Systemic Circulation ◽

Preclinical Study ◽

Dose Finding ◽

Tumor Uptake ◽

Tumor Bearing ◽

Biodistribution Studies ◽

Novel Approach ◽

Dose Levels

Abstract BACKGROUNDPSMA-targeted radionuclide therapy (TRT) is a promising treatment for prostate cancer (PCa) but dose-limiting xerostomia can severely limit its clinical adaptation, especially when using alpha-emitting radionuclides. With [18F]DCFPyL as a surrogate for PSMA-TRT, we report a novel method to selectively reduce salivary gland (SG) uptake of systemically administered [18F]DCFPyL by immediate prior infusion of non-radioactive standard of [18F]DCFPyL (DCFPyL) directly into the SG via retrograde cannulation. METHODSA dose-finding cohort using athymic nude mice demonstrated proof-of-principle that SG uptake can be selectively blocked by DCFPyL administered either locally via cannulation (CAN group) or systemically (SYS group). The experiments were repeated in a validation cohort of 22RV1 tumor-bearing mice. Submandibular glands (SMG) of CAN mice were locally blocked with either saline or DCFPyL (dose range: 0.01x to 1000x molar equivalent of the radioactive [18F]DCFPyL dose). The radioactive dose of [18F]DCFPyL was administered systemically 10 minutes later and the mice euthanized after 1 hour for biodistribution studies. Toxicity studies were done at up to 1000x dose. RESULTSIn the dose-finding cohort, the SYS group showed a dose-dependent 12-40% decrease in both the SMG T:B and the kidney (tumor surrogate). Mild blocking was observed at 0.01x, with maximal blocking reached at 1x with no additional blocking up to 1000x. In the CAN group, blocking at the 0.1x and 1x dose levels resulted in a similar 42-53% decrease, but without the corresponding decrease in kidney uptake as seen in the SYS group. Some evidence of “leakage” of DCFPyL from the salivary gland into the systemic circulation was observed. However, experiments in 22RV1 tumor-bearing mice at the 0.1x and 1x dose levels confirm that, at the appropriate blocking dose, SG uptake of [18F]DCFPyL can be selectively reduced without affecting tumor uptake and with no toxicity.CONCLUSIONOur results suggest that direct retrograde instillation of DCFPyL into the SG could predictably and selectively decrease salivary uptake of systemically administered [18F]DCFPyL without altering tumor uptake, if given at the appropriate dose. This novel approach is easily translatable to clinical practice and has the potential to mitigate xerostomia, without compromising the therapeutic efficacy of the PSMA-TRT.

Download Full-text

Assessment of current approaches of starting dose selection and dose escalation for oncology biologics in first-in-patient trials.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e14093 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e14093-e14093

Author(s):

Kai Hsin Liao ◽

Xiaoying Chen ◽

Darrin M. Beaupre ◽

Donghua Yin ◽

Chandrasekhar Udata

Keyword(s):

Dose Escalation ◽

Dose Ratio ◽

Dose Selection ◽

Toxic Dose ◽

Number Of Patients ◽

Starting Dose ◽

The Us ◽

Us Fda ◽

Trial Efficiency ◽

Dose Levels

e14093 Background: Current approaches for starting dose selection for first-in-patient (FIP) trials of oncology biologics vary according to pharmacological properties and modality of the investigational agent. For biologics with immune agonistic properties, the FIP starting dose is typically based on the minimal anticipated biological effect level (MABEL). For non-immune activating biologics, the starting dose is typically based on allometric scaling of a threshold toxic dose determined in the most appropriate animal species. The aim of this work is to assess the performance of current approaches of FIP starting dose selection and dose escalation for oncology biologics. Methods: FIP clinical trials for oncology biologics licensed by the US FDA from 2010 to 2019 were analyzed to extract information related to starting dose and dose escalation. Source materials for the relevant FIP trials included the Drugs@FDA database, PubMed, and conference proceedings. The data were further analyzed to evaluate parameters related to appropriateness of the starting dose and dose escalation efficiency, which include the number of cohorts to reach the maximum tolerated dose [MTD] (or, when MTD was not identified, the highest human dose [HHD]) and the ratio of MTD/HHD to starting dose. Results: The 26 oncology biologics licensed by the US FDA between 2010 and 2019 included 8 ADCs/immunotoxins, 7 checkpoint inhibitors and 11 other biologics (monoclonal antibody, fusion protein or CD3 bispecific construct). The majority (69%) of these biologics were well tolerated without MTD identified in the FIP trials. All 26 FIP trials with biologics appeared to follow ICH S9 Guidance for starting dose selection, and the dose increment ranged from 1.2- to 10-fold. These FIP trials had a median of 6 cohorts (range: 3-10) to reach MTD (or HHD) from the starting dose. About 50% of these trials involved ≥ 6 cohorts to reach MTD (or HHD). The MTD/HHD to starting dose ratio was > 100 for 4 of the biologics. The median label dose to starting dose ratio was 10 (range: 1-3200), suggesting that a large number of patients in these FIP trials received subtherapeutic dose levels. Conclusions: Current approaches of starting dose selection and dose escalation led to a very low starting dose and many dose escalation cohorts for the FIP trials of a large portion of recently licensed oncology biologics. There exist opportunities to improve current approaches to increase FIP trial efficiency and reduce the number of patients receiving subtherapeutic dose levels in these trials.

Download Full-text

A Bayesian dose-finding design for outcomes evaluated with uncertainty

Clinical Trials ◽

10.1177/17407745211001521 ◽

2021 ◽

pp. 174077452110015

Author(s):

Matthew J Schipper ◽

Ying Yuan ◽

Jeremy MG Taylor ◽

Randall K Ten Haken ◽

Christina Tsien ◽

...

Keyword(s):

Phase I ◽

Phase I Trial ◽

Data Augmentation ◽

Maximum Tolerated Dose ◽

Dose Finding ◽

Continual Reassessment Method ◽

Number Of Patients ◽

Continual Reassessment ◽

Partially Observed ◽

Dose Limiting Toxicity

Introduction: In some phase I trial settings, there is uncertainty in assessing whether a given patient meets the criteria for dose-limiting toxicity. Methods: We present a design which accommodates dose-limiting toxicity outcomes that are assessed with uncertainty for some patients. Our approach could be utilized in many available phase I trial designs, but we focus on the continual reassessment method due to its popularity. We assume that for some patients, instead of the usual binary dose-limiting toxicity outcome, we observe a physician-assessed probability of dose-limiting toxicity specific to a given patient. Data augmentation is used to estimate the posterior probabilities of dose-limiting toxicity at each dose level based on both the fully observed and partially observed patient outcomes. A simulation study is used to assess the performance of the design relative to using the continual reassessment method on the true dose-limiting toxicity outcomes (available in simulation setting only) and relative to simple thresholding approaches. Results: Among the designs utilizing the partially observed outcomes, our proposed design has the best overall performance in terms of probability of selecting correct maximum tolerated dose and number of patients treated at the maximum tolerated dose. Conclusion: Incorporating uncertainty in dose-limiting toxicity assessment can improve the performance of the continual reassessment method design.

Download Full-text

Bayesian adaptive design of early-phase clinical trials for precision medicine based on cancer biomarkers

The International Journal of Biostatistics ◽

10.1515/ijb-2021-0009 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Shinjo Yada

Keyword(s):

Neural Network ◽

Clinical Trials ◽

Precision Medicine ◽

Early Phase ◽

Patient Specific ◽

Specific Gene ◽

Cancer Type ◽

Background Characteristics ◽

Number Of Patients ◽

Early Phase Clinical Trials

Abstract Cancer tissue samples obtained via biopsy or surgery were examined for specific gene mutations by genetic testing to inform treatment. Precision medicine, which considers not only the cancer type and location, but also the genetic information, environment, and lifestyle of each patient, can be applied for disease prevention and treatment in individual patients. The number of patient-specific characteristics, including biomarkers, has been increasing with time; these characteristics are highly correlated with outcomes. The number of patients at the beginning of early-phase clinical trials is often limited. Moreover, it is challenging to estimate parameters of models that include baseline characteristics as covariates such as biomarkers. To overcome these issues and promote personalized medicine, we propose a dose-finding method that considers patient background characteristics, including biomarkers, using a model for phase I/II oncology trials. We built a Bayesian neural network with input variables of dose, biomarkers, and interactions between dose and biomarkers and output variables of efficacy outcomes for each patient. We trained the neural network to select the optimal dose based on all background characteristics of a patient. Simulation analysis showed that the probability of selecting the desirable dose was higher using the proposed method than that using the naïve method.

Download Full-text

Phase I Dose-Finding Study of Weekly Single-Agent Patupilone in Patients With Advanced Solid Tumors

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.0981 ◽

2005 ◽

Vol 23 (36) ◽

pp. 9120-9129 ◽

Cited By ~ 84

Author(s):

Eric H. Rubin ◽

John Rothermel ◽

Fisseha Tesfaye ◽

Tianling Chen ◽

Martine Hubert ◽

...

Keyword(s):

Partial Response ◽

Solid Tumors ◽

Half Life ◽

Drug Exposure ◽

Dose Range ◽

Single Agent ◽

Dose Finding ◽

Advanced Solid Tumors ◽

Blood Concentrations ◽

Terminal Half Life

Purpose To evaluate the safety and maximum-tolerated dose (MTD) of weekly patupilone, a natural epothilone B, in patients with advanced solid tumors. Patients and Methods Patients were treated with patupilone (0.3 to 3.6 mg/m2) for 6 weeks on/3 weeks off or 3 weeks on/1 week off. Dose-limiting toxicities (DLTs), MTD, and pharmacokinetics were determined for each schedule of administration. Results Ninety-one patients were enrolled. The most common tumor types included ovarian, breast, and colon cancers. Doses of patupilone less than 2.5 mg/m2 using either the 6 weeks on/3 weeks off or the 3 weeks on/1 week off schedule were tolerated well. At higher doses, DLTs were observed using both dosing schedules, with diarrhea the most common DLT. The MTD for both treatment schedules was 2.5 mg/m2. After a short infusion, patupilone blood concentrations declined in a multiphasic manner with a terminal half-life of 4 days. Drug clearance was nonrenal and was not related to body-surface area. Over the dose range evaluated, systemic drug exposure was approximately dose proportional. Three patients achieved a partial response, and 31 patients had stable disease. Two patients experiencing a partial response had received prior taxane therapy. Conclusion Patupilone is well tolerated when administered at a dose of 2.5 mg/m2, using either a 6 weeks on/3 weeks off or a 3 weeks on/1 week off schedule. In contrast with murine studies, patupilone has a relatively prolonged terminal half-life in humans. The partial responses in patients previously treated with taxanes is consistent with promising preclinical results.

Download Full-text