Sutton, Surrey, United Kingdom

HEM ISMART-D: Trametinib + Dexamethasone + Chemotherapy in Children with Relapsed or Refractory Hematological Malignancies

HEM-iSMART is a master protocol with sub-protocols. The overarching objective is that introducing targeted therapy using a biomarker driven approach for treatment stratification may improve the outcome of children with R/R acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) It is characterized by a shared framework that allows for the investigation of multiple IMPs and generate pivotal safety and efficacy evidence within the sub-protocols to establish and define the benefits and risks of new treatments for children with R/R leukemia. Sub-Protocol D within HEM-iSMART, is a phase I/II, multicenter, international, open-label clinical trial designed to evaluate the safety, tolerability, pharmacokinetics (PK) and efficacy of trametinib in combination with dexamethasone, cyclophosphamide and cytarabine in children, adolescents and young with R/R ALL and LBL. Patients with actionable alterations in the RAS-RAF-MAPK pathway will be eligible for sub-protocol D including but not limited to KRAS, NRAS, HRAS, FLT3, PTPN11, MAP2K1, MP2K1 hotspot mutations, cCBL; NF1 del.

A Study of JNJ-79635322 in Participants With Relapsed or Refractory Multiple Myeloma or Previously Treated Amyloid Light-chain (AL) Amyloidosis

A Study of CPI-0209 in Patients With Advanced Solid Tumors and Lymphomas

Emerging evidence suggests that EZH2 is overexpressed in many cancer types and has a pivotal role in disease progression. This is a Phase 1/2, open-label, multi-center, FIH study designed to evaluate the safety and tolerability and preliminary clinical activity of CPI-0209, an EZH2/1 inhibitor as monotherapy in patients with advanced solid tumors and lymphomas. Phase 1 is composed of a CPI-0209 Dose Escalation period in patients with advanced tumors and aims to determine maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of CPI-0209 as monotherapy in patients with advanced tumors. Phase 2 is planned to evaluate safety and tolerability and antitumor activity of CPI-0209 in six disease-specific cohorts (M1 to M6). Patients in Cohorts M1, M2, M3, M5, and M6 will be enrolled at 10 to 29 patients per cohort, using a Simon 2-stage design. Cohort M4 will enroll up to 20 patients with lymphoma in a single-stage. The primary aim of Phase 2 part of the study is to evaluate the antitumor activity of CPI-0209, and characterize the safety and tolerability of CPI-0209 as monotherapy in patients with selected tumors. In Phase 2, two additional doses are planned to be evaluated in cohorts M2 and M3 in 2 stages: Stage 2a and Stage 2b. In Stage 2a approximately 20 patients will be enrolled per cohort and will be randomized 1:1 to receive 2 prespecified dose levels of CPI-0209 once daily. When protocol criteria for initiating Stage 2b will be fulfilled after completion of Stage 2a, then Stage 2b will be opened for enrolment of additional 10 patients in one or both dose arms in each of the two cohorts. Thus, up to 40 patients per cohort (M2 and M3) could be enrolled.

Safety and Efficacy of Ponatinib for Treatment of Pediatric Recurrent or Refractory Leukemias, Lymphomas or Solid Tumors

Gamma Delta T Cells in AML

A Translational Study of Single Agent Olaparib in the Treatment of Advanced Oesophagogastric Cancer

Gastric and oesophageal cancers are a significant health burden and are a leading cause of cancer related death. Despite improvements in survival over the last 4 decades overall the outcomes remain poor. In patients with advanced disease the outlook is particularly bleak with survival rates of less than one year with first line chemotherapy. New treatments are urgently needed to improve the poor survival rates in these cancers. Olaparib is a PARP inhibitor which blocks poly(ADP-ribose) polymerase (PARP) 1, an enzyme which is involved in repair of damaged DNA. By inhibiting PARP1 olaparib prevents repair of damaged DNA. Cells with unrepaired DNA cannot survive and die. This trial is designed to assess the efficacy and safety/tolerability of olaparib in patients with advanced oesophagogastric cancer. It will be conducted in two stages: - The first stage will evaluate the efficacy of olaparib in 27 patients. If 4 or fewer patients have control of their disease at 8 weeks then the trial for the olaparib arm will stop and no further patients will be recruited to the study. If 5-13 patients have control of their disease at 8 weeks then the study will progress to stage 2. If 14 or more patients have disease control at 8 weeks then a larger study may be opened in an unselected population. - The second stage will evaluate disease control in a further 27 patients. This is to allow identification of potential biomarkers of response.

KORTUC Phase II - Intra-tumoural Radiation Sensitizer in Patients With Locally Advanced/Recurrent Breast Cancer

Aim: To test a slow release gel containing a commonly available and inexpensive chemical (hydrogen peroxide) for safety and activity in sensitizing large cancerous lumps in the breast or armpit to a standard 3-week course of radiotherapy in patients with locally advanced or recurrent breast cancer. Background: Laboratory research and initial clinical trials conducted in Japan raises the possibility that a simple and inexpensive treatment based on a very dilute (0.5%) hydrogen peroxide injected into cancers under local anaesthetic greatly increases the effectiveness of standard doses of radiotherapy. The side effects appear to be limited to mild/moderate discomfort at the injection site for up to 24 hours in one-third of patients. Rapid, complete and durable tumour disappearance has been reported in 49/55 bulky breast cancers in Japanese women treated using this approach, a response that is at least 3 times the success rate of radiotherapy alone in our own patients and in a contemporary Japanese control population. The inventor, Prof Ogawa of Kochi University, has approached the investigators to lead the further clinical evaluation and commercial development, starting with the proposed early phase trials testing safety and anti-cancer activity described below. Design and methods: After numbing the skin with local anaesthetic, a specialist doctor (radiologist) or trained radiographer will use ultrasound to guide the injection of a small volume of dilute (0.5%) hydrogen peroxide solution into the tumour twice a week during 3 weeks of standard radiotherapy. The drug is suspended in a natural gel (1% sodium hyaluronate, licensed for treating stiff knee joints) that ensures its slow release over 48 hours. The injection procedure lasts for 10-15 minutes altogether. Tiny oxygen bubbles are released from the hydrogen peroxide which help the radiologist guide the injection of drug to the proper places under the skin. We have recently completed a safety study confirming the mildness of side effects in 12 patients, and we now wish to test activity against cancer in a randomised controlled trial in 184 patients. Patients participating in Phase II will either have standard radiotherapy or the same radiotherapy plus the drug under test. Neither the patient nor the doctor will choose who has which treatment, which is allocated randomly. Patient and public involvement: Independent Cancer Patient Voice, a patient advocate group in the field of cancer, is collaborating with the investigators on the research plan, commenting and advising on the content and clarity of the written proposal. This group plays a prominent role in promoting UK clinical research, being represented on the Trial Management Groups of several national randomised cancer clinical trials. Dissemination: The results of this study will be presented at scientific meetings and at meetings of the patient advocate group in order to judge if the results for safety and activity are promising enough to justify taking the research further.