There are limited research and literature on the trial management challenges encountered in running adaptive platform trials. This trial design allows both (1) the seamless addition of new research comparisons when compelling clinical and scientific research questions emerge, and (2) early stopping of accrual to individual comparisons that do not show sufficient activity without affecting other active comparisons. Adaptive platform design trials also offer many potential benefits over traditional trials, from faster time to accrual to contemporaneously recruiting multiple research comparisons, added flexibility to focus on more promising research comparisons via pre-planned interim analyses and potentially shorter time to primary results. We share here our experiences from a trial management perspective, highlighting the challenges and successes. We evaluated the operational aspects of making changes to these adaptive platform trials and identified both common and trial-specific challenges. The operational steps and challenges linked to both the addition of new research comparisons and stopping recruitment following pre-planned interim analysis were considered in our evaluation. Specific operational challenges in these adaptive platform protocols, additional to those in traditional two-arm trials, were identified. Key lessons are presented describing some of the solutions and considerations over conducting these trials. Careful consideration on the practicality of the protocol structure (modular versus single protocol), the longevity and continuity of trial oversight committees, and having clear clinical and scientific criteria for the addition of new research comparisons were identified as some of the most common challenges. Understanding the operational complexities associated with running adaptive platform protocols is paramount for their conduct, adaptive platform trials offer an efficient model to run randomised controlled trials and we are continuing to work to reduce further the effort required from an operational perspective. FOCUS4: ISRCTN Registry, ISRCTN90061546 . Registered on 16 October 2013. ISRCTN Registry, ISRCTN78818544 . Registered on 2 February 2004.
TPS9142 Background: Patients (pts) with solid tumors that progress on standard chemotherapy and/or immune checkpoint inhibitors experience limited efficacy with existing standard of care options. These pts have a significant unmet need, and novel agents that safely enhance treatment efficacy are needed. Magrolimab is a monoclonal antibody that blocks CD47, a "don't eat me" signal often overexpressed on solid tumor cells. Magrolimab blockade of CD47 induces macrophage-mediated phagocytosis of tumor cells and has shown preclinical activity and promising clinical efficacy in hematologic malignancies. Certain chemotherapies, including taxanes, enhance prophagocytic signals on tumor cells, leading to potential synergistic antitumor activity when combined with magrolimab. This study is evaluating the safety, tolerability, and efficacy of magrolimab with docetaxel in metastatic non-small cell lung cancer (mNSCLC), small cell lung cancer (mSCLC), and urothelial cancer (mUC). Methods: This open-label study includes a safety run-in and 3 phase 2 cohorts. Pts eligible for the safety run-in must have had ≥1 (mNSCLC, mSCLC) or 2 and not more than 3 (mUC) prior lines of systemic anticancer therapy in a locally advanced/metastatic setting and will be treated with magrolimab + docetaxel. In phase 2, pts must have either mNSCLC treated with platinum-based chemotherapy and/or an immune checkpoint inhibitor (ICI), mUC treated with prior systemic chemotherapy and/or an ICI, or mSCLC treated with platinum-based chemotherapy with or without an ICI in a locally advanced/metastatic setting. Pts refractory to prior taxane therapy or who have received a taxane within 12 months of study start are excluded. Pts who had prior treatment with CD47/SIRPα-targeting agents were also excluded. Magrolimab is administered intravenously (IV) as a 1-mg/kg priming dose on cycle 1 day 1 (C1 D1) to mitigate on-target anemia followed by 30 mg/kg on D8 and D15. Magrolimab 30 mg/kg is administered on C2 D1, D8, and D15 and 60 mg/kg on D1 for C3+. The recommended phase 2 dose (RP2D) is determined in the safety run-in, with de-escalation if prespecified dose-limiting toxicity criteria are met. Once the RP2D is determined, the phase 2 cohorts will follow the same dose schedule. Docetaxel 75 mg/m 2 is administered IV on D1 of each cycle. Reasons for treatment discontinuation may include unacceptable toxicity, disease progression, or pt/investigator choice to discontinue. The primary endpoints are incidence of adverse events by CTCAE v5.0 (safety run-in, phase 2) and investigator-assessed objective response rate by RECIST 1.1 (phase 2 cohorts). Secondary endpoints are magrolimab concentration vs time and antidrug antibodies (safety run-in, phase 2), progression-free survival and duration of response by RECIST 1.1, and overall survival (phase 2 cohorts). Planned enrollment is ≈116 pts. Clinical trial information: NCT04827576 .
Molecular characterisation of tumours is increasing personalisation of cancer therapy, tailored to an individual and their cancer. FOCUS4 is a molecularly stratified clinical trial for patients with advanced colorectal cancer. During an initial 16-week period of standard first-line chemotherapy, tumour tissue will undergo several molecular assays, with the results used for cohort allocation, then randomisation. Laboratories in Leeds and Cardiff will perform the molecular testing. The results of a rigorous pre-trial inter-laboratory analytical validation are presented and discussed.
Biomarker-guided trials have drawn considerable attention as they promise to lead to improvements in the benefit-risk ratio of treatments and enhanced opportunities for drug development. A variety of such designs have been proposed in the literature, many of which have been adopted in practice. Implementing such trial designs in practice can be challenging, and identifying those challenges was the main objective of a workshop organised by the MRC Hubs for Trials Methodology Research Network's Stratified Medicine Working Group in March 2017. Participants reflected on completed and ongoing biomarker-guided trials to identify the practical challenges encountered. Here, the key challenges identified during the workshop including those related to funding, ethical and regulatory issues, recruitment, monitoring of samples and laboratories, biomarker assessment, and data sharing and resources, are discussed. Despite the complexities often associated with biomarker-guided trials, the workshop concluded that they can play an important role in advancing the field of personalised medicine. Therefore, it is important that the practical challenges surrounding their implementation are acknowledged and addressed.
5559 Background: Despite aggressive therapy, over 70% of locally advanced squamous cell carcinomas of the head and neck (SCCHN) fail primary treatment. Salvage therapy with surgery, chemotherapy or brachytherapy alone or in combination has a 30–40% response rate, but few long-term survivors. Re-irradiation with concurrent chemotherapy for SCCHN has recently become a well established approach after two consecutive cooperative group studies were reported. Intensity Modulated Radiation Therapy (IMRT) is a new and safer way to deliver radiation therapy. This retrospective review evaluated the potential benefit and toxicity using every other week IMRT with concurrent chemotherapy. Design: Thirty-seven patients with locally recurrent SCCHN were evaluated. All patients received re-irradiation with IRMT every other week with concurrent weekly carboplatin (median AUC= 2) or cisplatin (60–100 mg/m 2 ) ± 5-FU (800–1000 mg/m 2 ) or paclitaxel 175mg/m 2 every three weeks. Patients received 6000 cGy at 200 cGy per fraction. Results: The median follow-up time was 12 months. The overall response rate was 75.7% with a complete response (CR) and partial response (PR) of 56.8% and 18.9%, respectively. Among complete responders, 33% recurred locally in a median time of 5 months. The Kaplan-Meier estimate of disease-free survival, progression-free survival, and overall survival at 48 months is 58%, 45%, and 28%, respectively. At the time of last follow-up, 51.4% of patients were still alive and 27.8% of patients had no evidence of disease. Grade 3 or 4 acute toxicities occurred in 20% of patients of which 13.3% were hematologic requiring either growth factors or delay in chemotherapy. No deaths occurred during the course of treatment. Long-term complications consisted of one patient with an esophageal stricture requiring repeated dilations, 2 patients with chronic dysphagia, and 2 patients developing a pharyngeal-cutaneous fistula, one of which died from a carotid blowout occurring 6 months after treatment. Conclusions: IMRT delivered every other week with concurrent platinum based chemotherapy produces good responses with only moderate toxicity in patients previously treated with radiation therapy for recurrent head and neck cancer. No significant financial relationships to disclose.
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