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Clinical Trial

Brentuximab Vedotin or Crizotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage II-IV Anaplastic Large Cell Lymphoma

Despite numerous treatment strategies over the last 20 years failure rates remain 25-30% for pediatric anaplastic large cell lymphoma (ALCL). Two novel agents that have demonstrated high response rates as single agents in ALCL will be studied in this trial. Brentuximab vedotin (previously known as SGN35; currently marketed under the brand name Adcetris) is an antibody-drug conjugate containing an anti-CD30 monoclonal antibody linked to a tubulin inhibitor (monomethylauristatin E). After binding CD30, a transmembrane receptor expressed on all ALCLs, brentuximab vedotin is internalized and the drug is released into the cytoplasm where it causes cell cycle arrest and apoptosis. Tubulin inhibitors are active agents in ALCL as evidenced by responses using vincristine and vinblastine. The response rate of brentuximab vedotin in patients with relapsed/refractory ALCL is impressive and the FDA has approved brentuximab vedotin for the treatment of patients with ALCL that have failed one line of therapy. Crizotinib is an orally bioavailable small molecule inhibitor of receptor tyrosine kinases including anaplastic large cell lymphoma kinase (ALK). ALK plays a central role in the pathogenesis of ALCL due to a chromosomal translocation that results in expression of an oncogenic kinase fusion protein. Crizotinib inhibits ALK phosphorylation resulting in antitumor activity. Crizotinib has also shown impressive response rates in patients with refractory/relapsed ALK positive ALCL. The primary aim of this pilot phase II study is to determine the toxicity and efficacy of the addition of two novel agents (brentuximab vedotin or crizotinib) to standard chemotherapy (best arm of ALCL99) in children with newly diagnosed ALCL. In this protocol, patients with newly diagnosed ALCL will be randomized to receive standard chemotherapy plus brentuximab vedotin (Arm BV) or standard chemotherapy plus crizotinib (Arm CZ). All patients will initially receive a 5 day prophase followed by 6 cycles of chemotherapy. The novel agent (either brentuximab vedotin or crizotinib) will start with Cycle 1 and be given in all 6 cycles. Each cycle lasts 21 days with the total therapy lasting approximately 19 weeks. Each arm will be evaluated for toxicity. Each arm will independently be evaluated for differences in EFS compared to historical data for ALCL99. A secondary aim of the trial will be to determine if minimal disease at diagnosis and/or minimal residual disease during treatment can identify patients at high risk of recurrence. Minimal disseminated disease (MDD) and minimal residual disease (MRD) will be measured using peripheral blood at 3 separate time points (diagnosis, after prophase, and after Cycle 1). The results from this pilot phase II study will provide necessary information to incorporate these novel agents into future trials and potentially improve the treatment of children with ALCL.

Clinical Trial

DCP-001, Use of a Clinical Trial Screening Tool to Address Cancer Health Disparities in the NCI Community Oncology Research Program (NCORP)

A clinical trial screening tool protocol has been developed to facilitate the formulation of research questions; particularly those evaluating factors related to populations that are underrepresented in clinical trials, and address cancer care disparities. This protocol is designed to allow the collection, storage and abstraction of clinical and demographic data obtained during the screening process, using the Oncology Patient Enrollment Network (OPEN), the same informatics system used by investigators participating in NCI-sponsored trials. The protocol is not a scientific study; rather, a method to implement the screening tool and allow the collection and analyses of expanded data with informed consent. The tool, based on a screening log successfully used within the NCI Community Cancer Centers Program (NCCCP)5, has been streamlined and integrated into the sites workflow by using OPEN.

Clinical Trial

Carvedilol in Preventing Heart Failure in Childhood Cancer Survivors

Heart failure [HF], is one of the leading causes of late morbidity and premature death after successful treatment of childhood cancer with anthracycline chemotherapy. In fact, childhood cancer survivors are at a 15-fold increased risk of developing HF compared to age-matched healthy controls. The risk is higher among those exposed to anthracyclines at a young age, and among those with concomitant exposure to chest radiation. This anthracycline-related cardiotoxicity presents as a continuum from asymptomatic structural or functional cardiac abnormalities detected on imaging studies, to clinically symptomatic HF. There is a strong dose-dependent relationship between anthracycline chemotherapy exposure and HF risk. The incidence of symptomatic HF is < 5% with cumulative anthracyclines exposure of < 300 mg/m²; approaches 20% at doses between 300 and 600 mg/m²; and exceeds 30% for doses > 600 mg/m². Overall, nearly two-thirds of children exposed to high-dose (HD) anthracyclines (300 mg/m²) develop asymptomatic cardiac abnormalities; these individuals are at risk for developing HF. Outcome following anthracycline-related HF is poor; 5-year overall survival rate is < 50%. Nearly 60% of all childhood cancer survivors carry a history of prior anthracycline exposure. The decades of life saved among the rapidly growing anthracycline-exposed childhood cancer survivors, makes it imperative that we develop strategies (informed by the pathogenic basis of anthracycline-related cardiotoxicity) to reduce the risk of HF in the vulnerable populations. Anthracycline cardiotoxicity results from direct cardiac injury due to formation of free radicals; this injury initiates cardiac remodeling and subsequent deterioration of left ventricular (LV) function. ß-blockade or angiotensin-converting enzyme (ACE)-inhibition have been successfully used to prevent HF in adult non-oncology populations with asymptomatic LV dysfunction, as well as in pediatric non-oncology populations with a genetic predisposition to HF (but with preserved cardiac function at the time of intervention). There is increasing evidence supporting a comprehensive reversal of parameters used to measure cardiac remodeling, with the use of third generation ß-blockers such as carvedilol (combined ß1, ß 2, 1 blockade) when compared with ACE inhibitors (afterload reduction alone) following exposure to cardiotoxic agents (such as HD-anthracyclines). However, despite clear physiologic rationale, as well as evidence of clinical efficacy in non-oncology populations, clinicians are reluctant to use pharmacologic intervention in childhood cancer survivors, primarily due to a paucity of randomized clinical trials that would provide evidence for benefit from such an intervention. We address this gap in the proposed trial: a randomized, double-blind, placebo-controlled Phase 2b trial in asymptomatic childhood cancer survivors with prior exposure to HD-anthracyclines ( 300 mg/m2). This study will provide critical information regarding a physiologically plausible pharmacological risk reduction strategy for childhood cancer survivors at high risk for developing anthracycline-related HF. The proposed intervention has the potential to significantly reduce ongoing cardiac injury via interruption of neurohormonal systems responsible for LV remodeling, resulting in improved cardiac function and decreased risk of HF. The intervention is informed by previous studies demonstrating efficacy in pediatric and adult non-oncology populations, yet remains unstudied in the pediatric oncology population. The intervention will rely on reproducible and clinically relevant echocardiographic and blood biomarkers of early cardiac remodeling. Finally, the proposal leverages the well-established clinical trials network of the Children¿s Oncology Group (COG), allowing participation by geographically diverse patient populations.

Clinical Trial

Phase I/II Study of BLZ945 Single Agent or BLZ945 in Combination With PDR001 in Advanced Solid Tumors

This study is a FIH, open-label, multi-center, phase I/II, study which consists of a phase I dose escalation part of BLZ945 as single agent and in combination with PDR001, where two dosing regimens of BLZ945 will be evaluated. Once the MTD/RP2D for BLZ945 as a single agent is established, a phase II may commence, if signs of activity have been detected. Once the MTD/RP2D for BLZ945 in combination with PDR001 is established, a phase II part will commence. BLZ945 will be administered orally and PDR001 will be administered i.v. every four weeks until patient experiences unacceptable toxicity, progressive disease and/or treatment is discontinued at the discretion of the Investigator or the patient.

Clinical Trial

Sorafenib Induced Autophagy Using Hydroxychloroquine in Hepatocellular Cancer

The goal of this study is to validate a combined panel of methylation and mutation markers for the detection of bladder cancer in a prospective multicenter study. We will assess the added predictive accuracy of the methylation markers over the accuracy of bladder cancer detection using known clinical risk factors alone. In the future, careful selection of patients for initial diagnostic cystoscopy may lead to a major cost reduction and reduced patient burden.

Clinical Trial

Chemopreventive Effects of Epigallocatechin Gallate (EGCG) in Colorectal Cancer (CRC) Patients

Randomized, controlled pilot trial of patients with histological documentation of primary colon or rectal adenocarcinoma with resectable cancer, who have not received any treatments for cancer. If patient is a candidate for surgical resection, with no planned neoadjuvant chemotherapy, then the patient is eligible. All eligible subjects will be consented prior to surgery.