Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Recurrence

Lymphoma

Lymphoma, Mantle-Cell

Lymphoma, B-Cell

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphoma, Non-Hodgkin

B-cell Lymphoma

Lymphosarcoma

Mantle Cell Lymphoma

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Tisagenlecleucel

Ibrutinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Antineoplastic Agents, Immunological

Tyrosine

Single-arm study investigating combination of ibrutinib and Tisagenlecleucel treatment

ibrutinib and Tisagenlecleucel

Michael Dickinson

This is an open label, multi-center, single-arm, phase II study investigating the efficacy and safety of the combination of ibrutinib and Tisagenlecleucel in twenty patients with relapsed or refractory Mantle Cell Lymphoma (MCL) or who had sub-optimal response to standard therapy in the presence of TP53 mutation.

Clinical Trial to Assess The Efficacy and Safety of the Combination of Tisagenlecleucel And Ibrutinib in Mantle Cell Lymphoma

A Phase II, Open-Label, Single Arm Trial to Assess The Efficacy and Safety of the Combination of Tisagenlecleucel And Ibrutinib in Mantle Cell Lymphoma

Through monitoring of the incidence, nature and severity of adverse events (graded according to NCI CTCAE v5.0), Serious Adverse Events, dose interruptions and dose reductions of ibrutinib

Measured through aggregate measure of peripheral blood/or bone marrow flow cytometry, PCR and ctDNA

By monitoring for patient death due to any cause

Novartis

Peter MacCallum Cancer Centre, Australia

Diseases and Abnormalities at or Before Birth

Nutritional and Metabolic Diseases

Syndrome

Li-Fraumeni Syndrome

Neoplastic Syndromes, Hereditary

Genetic Diseases, Inborn

DNA Repair-Deficiency Disorders

Metabolic Diseases

Eligible subjects have a confirmed germline TP53 mutation or variant, OR have a family history of LFS and clinically managed as a LFS patient, OR meet LFS diagnostic criteria including Classic, Chompret, and LFL (Birch and Eeles) criteria. Medical information contribution is required for participation in the study. Subjects also have options to contribute a one-time DNA sample, a blood sample for plasma and a stool sample every six months, as well as access to their residual clinical tissues.

Biological relative of subjects with germline TP53 mutation or variant (LFS), including first degree (siblings, parents) and second degree (grandparents, aunts, uncles) relatives. Negative for germline TP53 mutation or variant. Medical information contribution is required for participation in the study. Subjects also have options to contribute a one-time DNA sample, a stool sample, as well as access to their residual clinical tissues.

Household member of subjects with germline TP53 mutation or variant (LFS), sharing a living space (apartment or free-standing home) for at least 6 months prior to study enrollment. Medical information contribution is required for participation in the study. Subjects also have options to contribute a one-time stool sample.

No Intervention

Kara N Maxwell, MD, PhD

Miche Duvall

Suzanne P MacFarland, MD

Suzanne MacFarland, MD

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.

Context: 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%. There are 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, including study of genotype-phenotype correlations, enhanced cancer screening modalities, and novel treatment strategies for cancers that develop.

Objectives: In order to study important clinical issues in LFS, the primary objective of this biobank is to gather and store ongoing clinical data and biospecimens from patients with LFS and other potential germline TP53-associated syndromes. The investigators plan to use this biobank to study genotype-phenotype correlations in patients with inherited TP53 mutations, mechanisms of tumor formation, and methods of cancer screening.

Study Design: This study is a retrospective/prospective biobank containing clinical data and data and biospecimen. Patients for inclusion will be identified by query of our clinical electronic medical record from the Children's Hospital of Philadelphia (CHOP) and Penn Medicine (PENN) for patients followed in our respective clinics. In addition, patients will be recruited by ongoing prospective collection in clinic. Data collection, data entry and biobank maintenance, will be conducted by the investigators listed on this protocol at CHOP and at PENN through the Master Reliance Agreement. Future investigators and collaborators at other institutions will have access to samples and limited data by executing a written Data User Agreement and/or Materials Transfer Agreement with the biobank.

Setting/Participants: The biobank will be conducted at CHOP and PENN. Any infant, child, or adult with a germline TP53 mutation will be invited to participate. In addition, individuals with a diagnosis of LFS or LFL, who have been seen by a physician at Penn/CHOP or referred from outside physicians will be contacted for participation. To provide control group samples, unaffected family members and/or household members will also be recruited. Prospective enrollment into the biobank is planned to be an ongoing effort, without a fixed end date or target subject number. At minimum, however, the estimated number of recruitment is approximately 300 affected individuals and their family/household members along with their data and specimens.

Data/Specimen Collection Procedures and Frequency: The only required study procedure is the review of medical records. Optional study procedures include collection of germline DNA (via blood, saliva, urine, or hair), plasma collection, stool collection, and skin biopsies. Clinical data will be updated every 6 months. Subjects can opt-out of this follow-up process.

For affected patients (group 1), collection of biospecimens will occur either once (i.e., blood, buccal swabs, urine, skin fibroblasts), or every six months (i.e., plasma from blood, stool samples, and other specimens that are obtained and leftover as part of clinical care) . Unaffected family members (group 2) and household members (group 3) will only have samples requested once as per Schedule of Study Procedures (Group 3 subjects will not be asked for a germline specimen). None of these procedures are required for the subjects to participate in the study. Children \<18 years will complete procedures at CHOP, and adult participants will complete study procedures at PENN (adolescents and young adults seen at CHOP clinically may have their samples collected at CHOP even if over 18 years).

Li-Fraumeni Syndrome/TP53 Biobank

Clinical and Molecular Studies of Li-Fraumeni Syndrome and TP53-associated Disorders

Only a limited data set will be available to future users of the biobank. To access data and biospecimens within the biobank, the prospective recipient executes a written Data User Agreement with the biobank, which will prohibit any attempts to re-identify subjects. Limited data will then be transmitted to prospective researchers using downloaded Excel compatible file formats. PHI will be maintained within the database as part of the consent process, in a partitioned and protected fashion (not available to future investigators) to permit the addition of updated clinical information into the biobank on a periodic basis. If for any reason the study is terminated, all data will be retained for six years, per CHOP policy A-3-9 for data retention. Following the end of data retention, data will be permanently de-coded and de-identified.

These data include but are not limited to family history, cancer history, genetic testing, and cancer treatment.

Children's Hospital of Philadelphia

Abramson Cancer Center at Penn Medicine

MD, PhD

Leukemia

Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Leukemia, B-Cell

Chronic Disease

Hematologic Diseases

Disease Attributes

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

Chromosome 17p Deletion

Pembrolizumab

Fludarabine

Fludarabine phosphate

Immunomodulating Agents

Immune Checkpoint Inhibitors

Ibrutinib, Fludarabine, and Pembrolizumab combination therapy will be administered in participants with High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). Ibrutinib will be administered daily by mouth starting cycle -3 at 420 mg until end study or disease progression or intolerable side effects occur. Fludarabine will be administered intravenously only on cycle -2 at 25mg/m\^2 x5 days. Pembrolizumab will be administered intravenously every 3 weeks at 200 mg starting from cycle 1 through cycle 17 or 1 year of immunotherapy phase.

Ibrutinib will be administered daily by mouth starting cycle -3 at 420 mg until end study or disease progression or intolerable side effects occur.

Fludarabine will be administered intravenously only on cycle -2 at 25mg/m\^2 x5 days.

Pembrolizumab will be administered intravenously every 3 weeks at 200 mg starting from cycle 1 through cycle 17 or 1 year of immunotherapy phase.

Adrian U Wiestner, M.D.

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.

Background:

This study investigates the combination of ibrutinib, fludarabine and pembrolizumab for treatment of CLL. 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. High-risk CLL is defined by relapsed/refractory disease status, or the presence of high-risk mutations, such as deletion 17p, TP53, and NOTCH1. While the cause of CLL is still unclear, studies have indicated critical factors required for the tumor cells. First, CLL cells grow and survive because they receive signals through the B-cell receptor (BCR); and second, CLL cells benefit from interactions with other cells, especially T cells.

The stimulation through the BCR can be blocked by ibrutinib, which is an oral drug that selectively inhibits Bruton's tyrosine kinase (BTK). In clinical trials, ibrutinib demonstrated safety and high response rates in patients with high-risk disease. Ibrutinib has gained FDA approval as a treatment for CLL regardless of prior treatment or cytogenetic status. However, single-agent ibrutinib has limitations; the drug does not eliminate all tumor cells and, with time, the tumor cells may become resistant. Therefore, combination of ibrutinib with other drugs could be beneficial.

Objectives:

-To investigate the rate of complete response to ibrutinib, short course fludarabine and pembrolizumab.

Key eligibility criteria:

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.

Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

A Phase II Study Of Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Rate of complete response with combination ibrutinib, fludarabine, and pembrolizumab in patients with high-risk and/or relapsed/refractory chronic lymphocytic leukemia and small lymphocytic leukemia. Response assessments defined by IWCLL 2008 guidelines incorporating the 2012 and 2013 clarifications for patients treated with kinase inhibitors. Complete response defined as: Lymphadenopathy is none \> 1.5 cm; No Splenomegaly or Hepatomegaly; Blood Lymphocytes \<4000/uL; Bone Marrow is normocellular, \<30% lymphocytes, no B-lymphoid nodules; Platelet count \>100,000/uL; Hemoglobin \> 11.0 g/dL and Neutrophils \>1500/uL. Partial response is defined by meeting 2 criteria: Lymphadenopathy decrease \> or = 50%; Splenomegaly or Hepatomegaly decrease \> or = 50%; Blood Lymphocytes decrease \> or = 50% from baseline; Platelet is \> 100,000/uL or increase \> or = 50% over baseline; Hemoglobin is \> 11.0 g/dL or increase \> or = 50% over baseline; Neutrophils is \> 1500/uL or increase \> or = 50% over baseline.

Tolerability of the combination regimen, Overall response rate (ORR), Duration of response (DOR), Best response, Minimal residual disease (MRD) status, Progression-free survival (PFS), Overall survival (OS), To explore the biologic effects on B- and T-cell subsets and function, To identify predictors of clinical response.

National Heart, Lung, and Blood Institute (NHLBI)

Ibrutinib, Fludarabine, and Pembrolizumab in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Adrian Wiestner, M.D., Ph.D., Principal Investigator

Includes all participants that completed the 1 year evaluation

Number of Participants With Complete Response of the Combination of Ibrutinib, Fludarabine, and Pembrolizumab in Patients With High-risk and/or Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Leukemia

Tolerability, Response and Best Response, Survival

Conditioning Phase (12 Weeks)

Immunotherapy Phase (1 Year)

Follow-up Phase (Extension Study)

Venetoclax

Venetoclax will be administered orally once daily (QD) beginning with a dose-titration phase. The initial venetoclax dose is 20 mg QD. After 1 week of treatment at 20 mg QD, the dose will be escalated to 50 mg QD followed by subsequent increases, each after 1 week, to 100 mg QD, 200 mg QD and the maximum dose of 400 mg QD. Participants may continue to receive venetoclax for up to 2 years provided they continue to tolerate the drug, have no evidence of disease progression (based on investigator's assessment), do not have unacceptable toxicity, and do not meet any of the criteria for discontinuation.

In countries where venetoclax is not commercially available, participants who continue to derive benefit after 2 years of treatment may be able to extend their treatment for up to 2 additional years, plus one additional year until the venetoclax extension study was open, determined on a case by case basis.

AbbVie Inc.

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.

Following the Screening period, all eligible participants initiate venetoclax on a once daily (QD) dosing schedule. To mitigate the risk for tumor lysis syndrome (TLS), dosing will start with a 5-week dose titration phase.

Participants may receive venetoclax for up to 2 years provided they continue to tolerate the drug, have no evidence of disease progression (based on investigator assessment), do not have unacceptable toxicity and do not meet any of the criteria for subject discontinuation. In countries where venetoclax is not commercially available, participants who continued to derive benefit after 2 years of treatment may extend their treatment for up to 2 additional years in an extended access phase. Participants in the extended access phase of this study who continue to derive benefit from venetoclax after the 2-year extension and are transferring to the venetoclax extension study, Study M19-388 (NCT03844048), may remain in Extended Access for up to 1 additional year or until the extension study is approved and initiated at the site, whichever is sooner.

A Study to Evaluate the Efficacy of Venetoclax Monotherapy in Relapsed/Refractory Participants With Chronic Lymphocytic Leukemia (CLL)

Open-Label, Single Arm, Phase 3b, Multi-Center Study Evaluating the Efficacy of Venetoclax (ABT 199) in Relapsed/Refractory Subjects With Chronic Lymphocytic Leukemia (CLL)

AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.

Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 modified IWCLL NCI-WG criteria.

CR required all of the following:

* Peripheral blood lymphocytes \< 4000/μL
* Absence of lymphadenopathy by physical examination and computed tomography scan
* No hepatomegaly or splenomegaly by physical examination
* Absence of disease or constitutional symptoms (unexplained fevers \> 38°C, drenching night sweats, \> 10% weight loss in last 6 months)
* Blood counts above the following:

  * Neutrophils \> 1500/μL
  * Platelets \> 100,000/μL
  * Hemoglobin \> 110 g/L
* Bone marrow at least normocellular for age, \< 30% lymphocytes.

CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.

Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 modified IWCLL NCI-WG criteria.

CR required all of the following:

* Peripheral blood lymphocytes \< 4000/μL
* Absence of lymphadenopathy by physical examination and computed tomography scan
* No hepatomegaly or splenomegaly by physical examination
* Absence of disease or constitutional symptoms (unexplained fevers \> 38°C, drenching night sweats, \> 10% weight loss in last 6 months)
* Blood counts above the following:

  * Neutrophils \> 1500/μL
  * Platelets \> 100,000/μL
  * Hemoglobin \> 110 g/L
* Bone marrow at least normocellular for age, \< 30% lymphocytes

CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.

Overall response rate was defined as the percentage of participants with an overall best response of CR, CRi, nodular partial remission (nPR), or confirmed partial remission (PR) based on the 2008 modified IWCLL NCI-WG criteria assessed by the investigator.

CR and CRi are defined above. nPR is defined as for CR but bone marrow nodules could be identified histologically.

For PR at least 2 of the following must be met:

* 50% decrease in peripheral blood lymphocyte count from the Baseline value;
* 50% reduction in lymphadenopathy;
* 50% reduction in the size of the liver and/or spleen (if abnormal prior to therapy);

In addition at least 1 of the following criteria must be met:

* Neutrophils \> 1,500/μL or ≥ 50% improvement over Baseline;
* Platelets \> 100,000/μL or ≥ 50% improvement over Baseline;
* Hemoglobin \> 11.0 g/dL or ≥ 50% improvement over Baseline without transfusions or exogenous growth factors.

PR must have been confirmed at least 7 weeks later.

Duration of response was defined as the time from the date of first response (CR, CRi, nPR, or PR) to the earliest date that progressive disease (PD) was objectively documented (radiographic or clinical) or death. Duration of response was analyzed by Kaplan-Meier (K-M) methodology. If a participant was still responding the data were censored at the date of the last available disease assessment prior to the data cutoff date.

Time to progression was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical). Participants who did not experience disease progression were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline disease assessments were censored at the first dose date plus 1 day. Time to progression was estimated using Kaplan-Meier methodology.

Progression-free survival (PFS) was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical) or death. Participants who did not experience disease progression or death were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline tumor assessment or clinical assessment for progression were censored at the date of first dose plus 1 day. Progression-free survival was analyzed by Kaplan-Meier methodology.

Overall survival (time to death) was defined as the time from the first dose date of venetoclax to the date of death. If a participant had not died the data were censored at the date when they were last known to be alive prior to the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology.

The MRD negativity rate is defined as the percentage of participants who had MRD negative status with less than one CLL cell per 10,000 leukocytes (\< 10-⁴) in peripheral blood and bone marrow. MRD was evaluated using next-generation sequencing. Per protocol, peripheral blood MRD assessments were to be collected from all participants at Week 24 and Week 48 and at the time the bone marrow assessment for confirmation of CR/CRi, and bone marrow (BM) MRD assessments were to be collected for participants undergoing a bone marrow procedure for confirmation of CR/CRi. Participants with no blood or BM MRD assessments were included in the calculation of MRD negativity rate as not having MRD negative status.

Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria.

CR required all of the following:

* Peripheral blood lymphocytes \< 4000/μL
* Absence of lymphadenopathy by physical examination and computed tomography scan
* No hepatomegaly or splenomegaly by physical examination
* Absence of disease or constitutional symptoms (unexplained fevers \> 38°C, drenching night sweats, \> 10% weight loss in last 6 months)
* Blood counts above the following:

  * Neutrophils \> 1500/μL
  * Platelets \> 100,000/μL
  * Hemoglobin \> 110 g/L
* Bone marrow at least normocellular for age, \< 30% lymphocytes.

CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.

The FACT-Leu is a 44-item, leukemia-specific questionnaire designed to assess health-related quality of life (HRQoL) and leukemia-specific symptoms using a core set of questions (Functional Assessment of Cancer Therapy-General; FACT-G), and a cancer site-specific leukemia subscale. Questions are scored on a scale from 0 (not at all) to 4 (very much).

FACT-G consists of 27 general items divided into 4 primary HRQoL domains: Physical Well-being (PWB; 7 items; score range 0-28), Social/Family Well-being (SWB; 7 items; score range 0-28), Emotional Well-being (EWB; 6 items; score range 0-24), Functional Well-being (FWB; 7 items; score range 0-28). The leukemia subscale consists of 17 items (score range 0-68) that assess patient concerns relating to leukemia. Three summary scales were calculated: FACT-Trial Outcome Index composed of the PWB, FWB, and leukemia subscale (score range 0-124); FACT-G (score range 0-108) and the FACT-Leu Total (range 0-176). Higher scores reflect better HRQoL.

The FACIT-Fatigue questionnaire measures fatigue and its effect on functioning and daily activities. The FACIT-Fatigue includes 13 items answered on a 5-point rating scale based on a 7-day recall period. Scores range from 0 to 52, with lower scores reflecting greater fatigue.

The EQ-5D-5L is a generic measure of health status consisting of two parts: a descriptive system consisting of 5 items and a visual analog scale (VAS).

The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The participant is asked to rate each dimension on 5 levels of severity (1: no problems, 2: slight problems, 3: moderate problems, 4: severe problems, 5: extreme problems).

The scores for the 5 dimensions are used to compute a single health utility index score representing the general health status of the individual. The health index score ranges from zero (defined as a health state equivalent to being dead) to 1 (full health).

The EQ-5D-5L is a generic measure of health status consisting of two parts, a descriptive system consisting of 5 items and a visual analog scale (VAS).

The VAS assesses the participant's self-rated overall health on a scale from 0 (worst health imaginable) to 100 (best health imaginable).

AbbVie

Participants received venetoclax on a once daily dosing schedule for up to 108 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. Participants who continued to derive benefit after 2 years of treatment may have continued venetoclax therapy for up to 3 additional years.

Age, Continuous

Age, Customized

Race/Ethnicity, Customized

Geographic Region

Prior Treatment With B-cell Receptor Inhibitor (BCRi)

Global Medical Services

The null hypothesis stated that the CR rate for BCRi-naïve participants would be ≤ 6%, based on the CR rate reported for current therapies at the time the study was designed, with an alternative hypothesis that the CR rate would be \> 6%. If the p-value for this test was \< 0.025, the null hypothesis would be rejected.

All enrolled participants treated with at least one dose of venetoclax who had not previously received treatment with BCRi

Complete Remission Rate in Participants Not Previously Treated With BCRi Therapy - Primary Analysis

All enrolled participants treated with at least one dose of venetoclax who were previously treated with BCRi

Complete Remission Rate in Participants Previously Treated With BCRi Therapy - Primary Analysis

All enrolled participants treated with at least one dose of venetoclax

Overall Response Rate (ORR) - Primary Analysis

Enrolled participants treated with at least one dose of venetoclax who had an overall response of CR, CRi, nPR, or confirmed PR.

Duration of Overall Response (DOR) - Primary Analysis

Enrolled participants treated with at least one dose of venetoclax

Time to Progression (TTP) - Primary Analysis

Progression-Free Survival (PFS) - Primary Analysis

Overall Survival (OS) - Primary Analysis

Physical well-being - Week 48

Physical well-being - Week 108

Social/family well-being - Week 48

Social/family well-being - Week 108

Emotional well-being - Week 48

Emotional well-being - Week 108

Functional well-being - Week 48

Functional well-being - Week 108

Leukemia subscale - Week 48

Leukemia subscale - Week 108

FACT-G total score - Week 48

FACT-G total score - Week 108

FACT-leukemia trial outcome index - Week 48

FACT-leukemia trial outcome index - Week 108

FACT-leukemia total score - Week 48

FACT-leukemia total score - Week 108

All enrolled participants treated with at least one dose of venetoclax with available data at each time point.

Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu)

Week 48

Week 108

Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue)

Change From Baseline in EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) Health Index Score

Change From Baseline in EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) Visual Analog Scale Score

Complete Remission Rate in Participants Not Previously Treated With BCRi Therapy - Final Analysis

Complete Remission Rate in Participants Previously Treated With BCRi Therapy - Final Analysis

Overall Response Rate (ORR) - Final Analysis

Duration of Overall Response (DOR) - Final Analysis

Time to Progression (TTP) - Final Analysis

Progression-Free Survival (PFS) - Final Analysis

Overall Survival (OS) - Final Analysis

Peripheral blood

Bone marrow

All enrolled participants who received at least one dose of venetoclax

Minimal Residual Disease (MRD) Negativity Rate - Primary Analysis

Minimal Residual Disease (MRD) Negativity Rate - Final Analysis

Participants received venetoclax on a once daily (QD) dosing schedule for up to 108 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.

In countries where venetoclax was not commercially available, participants who continued to derive benefit after 2 years of treatment could extend their treatment for up to two additional years plus one additional year until the venetoclax extension study was open.

Overall Study

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Hypersensitivity

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

The specific treatment regimen is as follows: Non-squamous NSCLC: almonertinib (110 mg/d) plus anlotinib (12mg/d) is started on the first day of each treatment cycle and administered every three weeks until disease progression or intolerable toxicity. Anlotinib was given for two weeks, followed by one week off.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Clinical Trial to Assess The Efficacy and Safety of the Combination of Tisagenlecleucel And Ibrutinib in Mantle Cell Lymphoma	NCT04234061	Mantle Cell Lym...	ibrutinib and T...	18 Years -	Peter MacCallum Cancer Centre, Australia
Li-Fraumeni Syndrome/TP53 Biobank	NCT04367246	Li-Fraumeni Syn... Li-Fraumeni-Lik...	No Intervention	-	Abramson Cancer Center at Penn Medicine
Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma	NCT03204188	B-Cell Chronic ... B-Lymphocytic L... Chronic Lymphoc... Leukemia, Chron... Leukemia, Chron... Leukemia, Lymph... Leukemia, Lymph... Lymphocytic Leu... Lymphocytic Leu...	Ibrutinib Fludarabine Pembrolizumab	18 Years -	National Institutes of Health Clinical Center (CC)
Li-Fraumeni Syndrome/TP53 Biobank	NCT04367246	Li-Fraumeni Syn... Li-Fraumeni-Lik...	No Intervention	-	Abramson Cancer Center at Penn Medicine
A Study to Evaluate the Efficacy of Venetoclax Monotherapy in Relapsed/Refractory Participants With Chronic Lymphocytic Leukemia (CLL)	NCT02756611	Chronic Lymphoc...	Venetoclax	18 Years - 99 Years	AbbVie
Almonertinib Combined With Anlotinib as First-line Treatment for Advanced Non-small Cell Lung Cance	NCT06043973	Advanced Non-sm...	almonertinib	18 Years - 75 Years	Qianfoshan Hospital
Li-Fraumeni Syndrome/TP53 Biobank	NCT04367246	Li-Fraumeni Syn... Li-Fraumeni-Lik...	No Intervention	-	Abramson Cancer Center at Penn Medicine
Camrelizumab Plus Fluzoparib for TP-53 Mutated Endometrial Cancer	NCT06413992	Endometrial Car... TP53 Mutation Recurrent or Me...	Fluzoparib Camrelizumab paclitaxel (alb... Carboplatin inj... Carboplatin External irradi...	18 Years -	Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Camrelizumab Plus Fluzoparib for TP-53 Mutated Endometrial Cancer	NCT06413992	Endometrial Car... TP53 Mutation Recurrent or Me...	Fluzoparib Camrelizumab paclitaxel (alb... Carboplatin inj... Carboplatin External irradi...	18 Years -	Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Maintenance Treatment With Bevacizumab and Atezolizumab for Ovarian Cancer	NCT04510584	Ovarian Endomet... Fallopian Tube ... Primary Periton... TP53 Mutation	Atezolizumab Bevacizumab	18 Years -	University Health Network, Toronto

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