24 Clinical Trials for Various Conditions
This study will evaluate the efficacy and safety of venetoclax and obinutuzumab (VEN + G) compared with fludarabine + cyclophosphamide + rituximab or bendamustine + rituximab (FCR/BR) in FIT participants (FIT is defined by a cumulative illness rating scale \[CIRS\]/score of ≤6 and a normal creatinine clearance of ≥70 mL/min) with previously untreated CLL without DEL(17P) or TP53 mutation requiring treatment. Eligible participants will be randomly assigned in a 1:1 ratio to receive either VEN + G (Arm A) or FCR/BR (Arm B).
Purpose This study is an 'N-of-one' observational study focusing on individuals with a hereditary predisposition to cancer due to a genetic mutation in the TP53 gene. An individual with this mutation has a \>90% chance of developing many different forms of cancer in their lifetime. Since germline TP53 gene mutation carriers are highly susceptible to cancer, cancer prevention strategies and early cancer detection strategies are crucial. Unfortunately, the current standard of care for monitoring germline TP53 gene mutation carriers for early signs of cancer is yearly MRI scans and intermittent blood draws. Villani et al. showed that standard monitoring is inadequate and introduced a more sophisticated protocol for early cancer detection. We extended the Villani et al. protocol to include a number of markers for early detection and are currently vetting their utility, in terms of their inherent variability, patient tolerability of frequent interrogation, and ability to show changes that might indicate a need for further examination. In addition to the markers being collected, important covariate information, such as diet, sleep, and activities are being collected (via, e.g., wearable wireless devices) in order to take them into account in assessing the levels of the markers at a single data collection time or over time. One important aspect of the protocol is to identify changes, rather than specific levels, in marker status over time for an individual that might be indicative of tumor formation, essentially exploiting the concept of 'personalized thresholds' discussed by Drescher et al. If any indication of the presence of a cancer, tumorigenic process, or general sign of ill-health is observed, the protocol calls for a discussion of the findings among the research team, followed by a discussion between the clinical lead on the research team and the primary care provider and/or specialists overseeing a participating patient's care, possible validation of the assay(s) motivating the discussions, and a decision on how to intervene on the part of the primary care provider and/or specialists.
Background: - Li-Fraumeni syndrome (LFS) is a genetic condition that increases the risk for some types of cancer. LFS may lead to cancer of the bone or connective tissue, breast, and brain. It may also increase the risk for certain types of leukemia and other cancers. The only known cause of LFS is a change (called a mutation ) in a gene known as TP53. However, not all people with LFS have a TP53 mutation. Researchers want to study other possible genetic causes of LFS, and factors that may increase or decrease cancer risk in people with the syndrome. Objectives: * To learn more about the types of cancers that occur in individuals with LFS. * To study the role of the TP53 gene in the development of cancer. * To look for other possible genes that cause LFS * To study the effect of LFS diagnosis on families. * To determine if environmental factors or other genes can change a person s cancer risk associated with LFS. Eligibility: * Individuals with a family or personal medical history of cancers consistent with LFS. * Individuals with a family or personal medical history of cancers that does not meet the diagnosis of LFS, but the history is suggestive for LFS (meets the diagnosis for the so-called Li-Fraumeni like syndrome) * Individuals with certain rare cancers * Individuals with a family or personal history of a TP53 gene mutation, with or without related cancer(s). Design: * Participants will fill out a medical history questionnaire and a family history questionnaire. * Blood samples will be collected for DNA and for storage. Cheek cell samples may be collected if blood cannot be obtained for DNA. Participants can choose to have or not have cancer screening with blood tests, imaging studies, and other exams. * Participants will complete questionnaires about their worries about cancer, stress levels, and coping strategies. Diet and physical activity questionnaires will also be given. Other psychological tests may be given as needed. * Participants will be monitored for several years, with regular followup visits to the National Institutes of Health, if indicated. Any changes in health or cancer status will be recorded.
Background: Gastrointestinal (GI) cancer affects the organs (such as the stomach, large and small intestine, pancreas, colon, liver, and biliary system) of the digestive tract. In some participants who have had surgery for GI cancer, blood tests show that the cancer has spread despite being unable to be identified by scans. Certain gene mutations (changes) in GI cancer (such as KRAS or TP53) can be targeted by T cells, a type of immune cell, in individuals with specific HLA types (genes that help proteins in the body know what is self and non-self). Researchers want to see if they can stop GI cancer from returning or spreading in people with these gene mutations and specific HLA types. Objective: To test therapy with modified T-cells to prevent or delay the return of GI cancer after standard treatment. T-cells play a role in the body s immune system. Eligibility: People aged 18 to 72 years with GI cancer that was treated with standard therapy and is not seen on imaging scans. They must have specific gene mutations and HLA types. They also must have certain clinical or blood tests showing the cancer is spreading (elevating CA19-9 or detectable ctDNA). Design: Participants will be divided into 2 groups. Participants nor the study team can choose what Group to participate in; this is done by randomization , like flipping a coin. Participants will have a 1-to-1 chance of being in Group 1 or Group 2. Group 1 will receive T-cell therapy. Their own T-cells will be collected. In a lab, the cells will be combined with a virus that carries a protein to target cancer cells. Group 1 participants will stay in the hospital for 3 weeks or more. They will have chemotherapy, and their modified T-cells will be infused through a tube attached to a needle inserted into a vein. Group 1 participants will visit the clinic every 3 months for 1 year and then every 6 months for 5 years. Then they will have follow-up visits for another 10 years under a different protocol. Group 2 participants will not receive treatment with T-cells. They will visit the clinic every 3 months for 1 year and then every 6 months for 5 years.
The aim of PERKA-812-003 study is to investigate the safety, pharmacokinetics and preliminary anti-tumor activity of treatment with NMS-03597812 as single agent in Relapsed/Refractory Acute Myeloid Leukemia (R/R AML) patients who have exhausted standard treatment, including a subset of patients with TP53 mutations. It is anticipated that combination with venetoclax will be further evaluated following a future protocol amendment, once the Recommended Range Dose (RDR) as single agent has been defined.
This study will assess the effect of a Proton Pump Inhibitor (PPI) (rabeprazole) on the pharmacokinetics (PK) of PC14586 and the effect of an H2-receptor antagonist (famotidine) on the PK of PC14586
The Phase 2 monotherapy portion of this study is currently enrolling and will evaluate the efficacy and safety of PC14586 (INN rezatapopt) in participants with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation. The Phase 1 portion of the study will assess the safety, tolerability and preliminary efficacy of multiple dose levels of rezatapopt as monotherapy and in Phase 1b in combination with pembrolizumab.
Li-Fraumeni Syndrome (LFS) and Li-Fraumeni-like (LFL) Syndrome are cancer predisposition syndromes due to germline aberrations in the TP53 gene. Patients with classical LFS have a lifetime malignancy risk between 80-90%, with 21% of those cancers occurring by the age of 15 years. There are established guidelines for screening patients with LFS that have led to earlier detection and treatment of cancer in this population. There are a number of important issues facing patients identified to have germline TP53 variations. First, with the advent of massively parallel sequencing, increasing numbers of patients are now being identified with a wide range of clinical phenotypes associated with germline TP53 mutations, and the natural history of these patients is less well understood. Second, surveillance for malignancy in LFS and other TP53-associated syndromes involves frequent laboratory and radiologic studies that are imperfect measures of disease onset; therefore, more specific, less invasive biomarker-driven screening methods are needed. Finally, studies to date have not yet identified whether tumors which form in LFS or other germline TP53-associated tumors have unique aberrations or signatures that could be exploited in precision medicine treatment of these patients. In order to study these important issues in LFS, this protocol will establish a TP53 Clinical Database and Biobank. The Investigator plans to use this biobank to study genotype-phenotype correlations in patients with LFS and other germline TP53-associated syndromes, mechanisms of tumor formation, and novel methods of cancer screening in this high risk population.
Background: Chronic lymphocytic leukemia and small lymphocytic lymphoma (hereby referred as CLL) are tumors of B cells. A subset of patients categorized as high-risk CLL has a poor clinical outcome when treated with conventional chemotherapy. This single-arm, phase II study investigates the combination of ibrutinib, fludarabine and pembrolizumab for treatment of CLL. Ibrutinib is an orally administered therapy for CLL. Fludarabine is a well-tolerated drug that has been widely used to treat CLL. Also, fludarabine can modulate CLL cells as well as immune cells that support the growth of CLL cells. Pembrolizumab recruits immune cells to attack CLL cells. With this approach we hope to achieve a greater reduction in CLL cells than with single agent ibrutinib and to restore healthier immune system that could contribute to durable responses. Objective: To investigate the rate of complete response to ibrutinib, short course fludarabine and pembrolizumab. Eligibility: Patients with active CLL meeting treatment indications defined by 2008 International Workshop on CLL (IWCLL) consensus guideline. High-risk CLL defined by one of the following: * Relapsed/refractory disease status, or * Presence of high-risk mutations regardless of prior treatment status: deletion 17p, TP53 mutation, NOTCH1 mutation, SF3B1 mutation, MYC aberration, or complex cytogenetics. Design: This is a single-arm, open-label phase II study. Timeline: Treatment on this study is given in cycles from cycle -3 to 17, then in months beyond cycle 17. Cycles -3 to -1 are 28-day cycles. Cycles 1 to 17 are 21-day cycles. After completion of 1 year of pembrolizumab, the time on study is by chronological months on study from starting pembrolizumab. Treatment plan: * Ibrutinib is given starting from cycle -3 and continuously until disease progression or intolerable side effects occur. * Fludarabine is given on D1-D5 on cycle -2 only * Pembrolizumab is given every 3 weeks starting from cycle 1 for 1 year. * Minimal residual disease will be measured at 2 years from cycle 1 to determine the need for long- term treatment with ibrutinib. * Previously-untreated patients who achieve minimal residual disease negativity will stop ibrutinib. * Patients who do not achieve minimal residual disease negativity or who has Relapsed/refractory CLL will continue ibrutinib.
The purpose of this study is to evaluate the efficacy of venetoclax monotherapy in participants with relapsed/refractory CLL with or without the 17p deletion or TP53 mutation, including those who have received prior treatment with a B-cell receptor inhibitor.
This study is to determine the response to acalabrutinib in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
This study is to evaluate the efficacy and safety of JAB-30355 in adult participants with advanced solid tumors harboring TP53 Y220C mutation.
Phase I Study of NT-175, an autologous T cell therapy product genetically engineered to express an HLA-A\*02:01-restricted T cell receptor (TCR), targeting TP53 R175H mutant solid tumors.
The purpose of this research study is to learn more about variants in the TP53 gene both associated with Li-Fraumeni Syndrome (LFS), a hereditary cancer risk condition, and TP53 variants found in the blood for other reasons (e.g. ACE/CHIP and mosaicism).
This pilot clinical trial studies the side effects of irradiated donor cells following stem cell transplant in controlling cancer in patients with hematologic malignancies. Transfusion of irradiated donor cells (immune cells) from relatives may cause the patient's cancer to decrease in size and may help control cancer in patients receiving a stem cell transplant.
This phase I trial studies the side effects of vaccine therapy and pembrolizumab in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment, that have failed prior therapy, and that cannot be removed by surgery. Vaccines made from a gene-modified virus may help the body build an effective immune response to kill tumor cells. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Giving vaccine therapy together with pembrolizumab may be a better treatment in patients with solid tumors.
Background: * Li Fraumeni Syndrome (LFS) is a highly penetrant, autosomal dominant cancer predisposition disorder. Four main cancer types including sarcoma, adrenocortical carcinoma, breast cancer, and malignant brain tumors commonly characterize LFS but the syndrome can include other cancers. * Metformin is an oral biguanide drug that is approved by the FDA for the treatment of type II diabetes. Metformin has been associated with reduced cancer risk in several epidemiologic studies and reduced cancer mortality in patients with type 2 diabetes. * Metformin decreases circulating insulin and IGF1, and promotes glucose uptake in skeletal muscle and inhibits gluconeogenesis in the liver. Elevations in circulating insulin and IGF1 levels have been associated with increased cancer risk. * Preclinical research in animal models shows that metformin may be more toxic in cancer cells that have lost p53 function. * Lifetime risk of cancer in LFS patients with germline TP53 mutations is estimated to be up to 70% by age 60, with women having excess lifetime cancer risk (up to 100%) compared to men (up to 80%). There are currently no approved chemopreventive agents for patients with LFS. * Metformin has been shown to be safe and tolerable in diabetic and non-diabetics, and may be an ideal candidate for chemoprevention of cancer in this population. Objectives: * Determine the tolerability of oral daily metformin in patients with LFS caused by germline TP53 mutations. * Determine if 8 weeks of daily metformin administration has any effect on circulating IGF-1, insulin, and IGFBP3 Eligibility: * Must have a germline TP53 mutation and provide documentation of testing. * Must have adequate organ function. * Age greater than or equal to 18 years. Design: * This is a pilot study to assess the tolerability of daily oral metformin administration in patients with LFS caused by germline TP53 mutations and to study the effect of metformin on biomarker levels in these subjects. * In the absence of intolerable toxicity, a minimum of 22 patients will take metformin by mouth for a total of 14 weeks and then discontinue metformin for 6 weeks. The total time on study will be 20 weeks. * Patients will be assessed for biomarker levels (IGF-1, insulin, IGFBP3) by blood sample at baseline, and weeks 0 and 8.
Background: Nicotinamide riboside (NR) is a vitamin B3 dietary supplement. It may help improve muscle function, that may in turn may improve a person s exercise capacity. Researchers want to study how skeletal muscle responds to NR in an individual who has Li-Fraumeni Syndrome and slow muscle energy recovery after exercise. Objective: To study how nicotinamide riboside affects skeletal muscle after exercise. Eligibility: One person at least 18 years old with Li-Fraumeni syndrome and a certain gene mutation Design: The participant will be screened with a medical history, physical exam, and blood and urine tests. The participant may also have a heart test. The participant will maintain their regular diet and supplements during the study. The participant will take the study drug as 1-4 tablets twice a day for 12 weeks. The participant may be contacted with reminders and questions about side effects. The participant will have 4-5 visits over 18-30 weeks. At visits, the participant will repeat screening tests. At some visits they will also have: * Ultrasound of the heart with a wand placed on the chest. * Test of oxygen used at rest and exercise, while wearing a face mask. * Exercise test on a treadmill or bicycle with electrodes on the skin. * Magnetic resonance spectroscopy. The participant will have no caffeine for 12 hours. Then they will lie in a machine for about 2 hours. Sometimes they will lie still. Sometimes they will be asked to move. Health questionnaire The participant may have a skin sample taken by needle. The participant will be withdrawn from the study if they become pregnant.
Phase 1 dose escalation and expansion study of CLSP-1025, a first-in-class HLA-A\*02:01 specific T cell engager (TCE) targeting solid tumors that harbor the p53 R175H mutation.
This is a Phase 1b open-label, single arm, multicenter, study of ALRN-6924 as a chemoprotection agent in patients with TP53-mutated HER2- breast cancer (stages IIa to IIIb) receiving neoadjuvant or adjuvant chemotherapy with doxorubicin, docetaxel, and cyclophosphamide (TAC). Chemotherapy affects cells that are dividing, whether they are tumor cells or healthy cells (including, bone marrow cells, hair follicle cells, and epithelial cells lining the gastrointestinal tract). ALRN-6924 is designed to stop cell division in healthy cells but not in tumor cells because they have a mutation of the TP53 gene. When this happens, tumor cells will still be destroyed by the chemotherapy but healthy cells that are not dividing may be spared from chemotherapy damage and the patient should have less side effects.
This is a phase II, open-label, prospective study of T cell receptor alpha/beta depletion (α/β TCD) peripheral blood stem cell (PBSC) transplantation for children and adults with hematological malignancies
This phase II trial studies how well fludeoxyglucose F-18 (18F-FDG) positron emission tomography (PET) and osimertinib works in evaluating glucose utilization in patients with EGFR activated glioblastoma. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 18F-FDG PET imaging may help to detect changes in tumor glucose utilization, which may allow investigators to obtain an early read out on the impact of osimertinib on recurrent glioblastoma patients whose tumors have EGFR activation.
Approximately 90% of children with malignant brain tumors that have recurred or relapsed after receiving conventional therapy will die of disease. Despite this terrible and frustrating outcome, continued treatment of this population remains fundamental to improving cure rates. Studying this relapsed population will help unearth clues to why conventional therapy fails and how cancers continue to resist modern advances. Moreover, improvements in the treatment of this relapsed population will lead to improvements in upfront therapy and reduce the chance of relapse for all. Novel therapy and, more importantly, novel approaches are sorely needed. This trial proposes a new approach that evaluates rational combination therapies of novel agents based on tumor type and molecular characteristics of these diseases. The investigators hypothesize that the use of two predictably active drugs (a doublet) will increase the chance of clinical efficacy. The purpose of this trial is to perform a limited dose escalation study of multiple doublets to evaluate the safety and tolerability of these combinations followed by a small expansion cohort to detect preliminary efficacy. In addition, a more extensive and robust molecular analysis of all the participant samples will be performed as part of the trial such that we can refine the molecular classification and better inform on potential response to therapy. In this manner the tolerability of combinations can be evaluated on a small but relevant population and the chance of detecting antitumor activity is potentially increased. Furthermore, the goal of the complementary molecular characterization will be to eventually match the therapy with better predictive biomarkers. PRIMARY OBJECTIVES: * To determine the safety and tolerability and estimate the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of combination treatment by stratum. * To characterize the pharmacokinetics of combination treatment by stratum. SECONDARY OBJECTIVE: * To estimate the rate and duration of objective response and progression free survival (PFS) by stratum.
PRECISION-NEC is a single-center, open-label, pilot feasibility study of molecularly defined subtypes of metastatic high-grade neuroendocrine carcinoma (HG-NEC). The hypothesis is that HG-NEC (excluding small cell carcinoma) can be segregated based on mutational analysis and that next generation sequencing (NGS)-based assignment of therapy is feasible and will potentially improve the outcomes.