Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Lymphoma

Lymphoma, Non-Hodgkin

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Glucocorticoids

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

NOXA IHC score \> 4; Bridging therapy was allowed but not containing chidamide; n=60.

NOXA IHC score \< 4; Bridging therapy was allowed but not containing chidamide; n=30.

NOXA IHC score \< 4; Bridging therapy containing chidamide alone or combination; n=30.

1. Chidamide monotherapy mode: Chidamide was administered for at least 6 times after leukapheresis, 10mg oral D1-4, 20mg oral D7 every 3 days to the beginning day of FC conditioning.
2. Chidamide combination mode: The combination of one or more of the following drugs in addition to chidamide is permitted: glucocorticoids, BTK inhibitors, chemotherapy, other previously used resistance drugs, etc.

Chidamide

Patients should be received FC regimen conditioning 3 to 5 days prior to CAR-T cell infusion. The recommended regimen is intravenous fludarabine (25-30 mg/m\^2) and cyclophosphamide (250-500 mg/m\^2) daily for 3 consecutive days. The clinician may also adjust the cleansing regimen according to the patient's actual situation.

Fludarabine and cyclophosphamide

A single infusion of CAR-transduced autologous T cells administered intravenously at a target dose of 100 × 10\^6 for Relma-cel or 2 × 10\^6/kg for Axi-cel. Other commercial CAR-T doses are determined by specific drug infusion instructions. The dose of experimental CAR-T was determined by the investigator. Infusion volume was calculated based on CAR-T cell density and recommended dose.

Anti-CD19 CAR-T cells

Weidong Han, Ph.D

Liang Wang

Wei Zhang, Ph.D

Zhitao Ying, Ph.D

Yuhua Li, Ph.D

Qingqing Cai, Ph.D

Liang Huang, Ph.D

Heng Mei, Ph.D

Aibin Liang, Ph.D

Ting Niu, Ph.D

Caixia Li, Ph.D

Huilai Zhang, Ph.D

Wenbin Qian, Ph.D

The previous research suggests that the low expression of NOXA protein may be an important biomarker for the treatment of drug resistance of chimeric antigen receptor-T (CAR-T) cells. Up regulating the expression of NOXA through histone deacetylase inhibitor (HDACi) can improve drug resistance and significantly improve the therapeutic effect of CAR-T cells. This study will enroll approximately 120 subjects with recurrent or refractory (r/r) B-cell non-Hodgkin's lymphoma (NHL). Those with high expression of NOXA will receive conventional CAR-T treatment (without chidamide bridging), and those with low expression of NOXA will be randomly assigned 1:1 to those without or containing chidamide bridging. The purpose of this study was to evaluate the clinical response and safety of chidamide bridging.

Background:

CAR-T cell therapy has been shown to be superior to conventional therapy in patients with r/r B-cell NHL. However, prior clinical studies and real-world data suggest that approximately 30-40% of cases of drug resistance still occur after CAR-T cell therapy, and approximately 50-60% of cases have recurrent disease progression over time of infusion. The investigators used genome-wide CRISPR/Cas9 to screen for CAR T-resistant cells and identified low NOXA expression as associated with CAR-T resistance. NOXA protein is a member of the Bcl2 protein family, which plays a critical role in P53-dependent apoptosis. The previous research suggests that the low expression of NOXA protein may be an important biomarker for the treatment of drug resistance of CAR-T cells. Through the verification of nearly 40 clinical samples previously treated with CAR-T, the investigators found that low NOXA expression was associated with poor prognosis. Meanwhile, animal experiments demonstrated that HDACi can up-regulate the expression of NOXA in tumor cells and significantly improve the efficacy of CAR-T therapy by reducing the incidence of resistance. The research was published in Signal Transduction and Targeted Therapy in 2022.

Objective:

The primary objective of the study was to evaluate whether chidamide bridging intervention improved clinical response to CAR-T in patients with r/r B-cell NHL. A secondary objective was to evaluate the safety of bridging therapy with chidamide and subsequent CAR-T infusion in above patients. The exploratory objective was to investigate the effect of chidamide intervention on NOXA expression.

Design:

This is a multicenter, prospective, controlled, open-label, phase Ⅰ/Ⅱ study. 120 patients with r/r B-cell NHL will be enrolled. Biopsy was performed before peripheral blood mononuclear cell (PBMC) collection, and NOXA expression level was detected by immunohistochemistry (IHC).

Patients with high NOXA expression (IHC score \> 4) were treated with conventional CAR-T process (n=60), including PBMC collection, bridging therapy (without chidamide), fludarabine and cyclophosphamide (FC) regimen conditioning, CAR-T cell infusion, efficacy evaluation and follow-up; Patients with low NOXA expression (IHC score 0 - 4) were randomly assigned 1:1 to conventional CAR-T group as mentioned earlier (n=30) or CAR-T group containing chidamide bridging therapy (n=30).

The bridging therapy regimen containing chidamide was divided into monotherapy and combination therapy. Chidamide combination intervention can be used in cases of high tumor burden, rapid progression of disease, symptoms of compression, involvement of specific sites or organs, and other burden reduction that need to be addressed. The combination of one or more of the following drugs in addition to chidamide is permitted: glucocorticoids, BTK inhibitors, chemotherapy, other previously used resistance drugs, etc.

In this study, commercial CAR-T cells (mainly Relma-cel, with Axi-cel or other commercial CAR-T cells also acceptable) or experimental CAR-T cells targeted at CD19 were acceptable.

If feasible, for the group with low NOXA expression, a secondary biopsy was performed at the same site to detect changes in NOXA expression before CAR-T infusion.

Chidamide Bridging for CAR-T Therapy

A Multiple Center Study on NOXA Expression-guided Randomized Chidamide Bridging Intervention in CAR-T Treated NHL Patients

For the group with low NOXA expression, a secondary biopsy was performed at the same site to detect changes in NOXA expression before CAR-T infusion. In the chidamide bridging group, the timing of secondary biopsy was arranged at least 6 times' chidamide therapy and before CAR-T infusion.

PFS is defined as the time between the date of CAR-T infusion and disease progression or death from any cause. At the time of statistical analysis of study endpoints, there were no PFS events, and data were truncated as the date of the last objective tumor evaluation. Patients who were lost to follow-up or withdrew informed consent will be included in the end point evaluation, with data truncated as the date of the last objective tumor evaluation.

AE is defined as any adverse medical event from the time between the date of randomization and the date of 12 months after CAR-T infusion. AE may be an adverse sign (including abnormal laboratory tests, etc.), symptom, or illness that is not related to the purpose of medication and is time-related to drug use, regardless of causality to the drug, such as long-term cytopenia, cytokine release syndrome, neurotoxicity, etc.

ORR was defined as the percentage of subjects who achieved complete response or partial response assessed by investigators and based on the Lugano 2014 assessment criterion. All subjects who do not meet objective response criteria by the data analysis deadline will be considered nonresponders. The source of this endpoint will only include the assessment of response obtained after CAR-T infusion and prior to any additional antitumor therapy.

CRR was defined as the percentage of subjects who achieved a CR assessed by investigators and based on the Lugano 2014 assessment criterion.

RFS was defined as the time between the date of CAR-T infusion and the date of first lymphoma recurrence (local, regional, distant metastasis) or death (whatever the cause) for subjects who received complete response after CAR-T infusion. For participants who remained alive and whose disease had not recurred, RFS was censored on the date of last visit/contact with disease assessments.

OS was defined as the time between the date of CAR-T infusion and death from any cause.

Chinese PLA General Hospital

Director of Biotherapeutic Department

Skin and Connective Tissue Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Carcinoma

Breast Neoplasms

Triple Negative Breast Neoplasms

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Cystadenocarcinoma, Serous

Cystadenocarcinoma

Breast Diseases

Skin Diseases

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Neoplasms, Glandular and Epithelial

Adenocarcinoma

Neoplasms, Cystic, Mucinous, and Serous

Ovarian Cancer

Ovarian Epithelial Cancer

Adenocarcinoma of the Appendix

Olaparib

Navitoclax

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Olaparib tablet will be administered alone for 14 days at a starting dose of 200 mg twice daily (bid). Subsequently olaparib will be administered continuously over 28 days at a fixed dose and the dose of navitoclax will be escalated. Navitoclax will be administered daily. The initial dose of olaparib 200 mg has been selected after considering the single agent Phase I/II dose based and on ongoing combination studies on expected toxicity and evidence for reduced PARP inhibition

Olaparib tablet will be administered alone for 14 days at a starting dose of 200 mg twice daily. Subsequently olaparib will be administered continuously over 28 days at a fixed dose and the dose of navitoclax will be escalated.

Olaparib tablet

For navitoclax, a lead-in of 7 days at 150 mg PO will be used prior to dose escalation. The DLT period for dose levels above DL 3 will include the 14-day olaparib alone lead-in, the 7 days combination with navitoclax at 150 mg and the first 28 day cycle of the combination of olaparib and navitoclax cycle at the full dose level dosing (49 days).

Helen Mackay

Helen MacKay, MD

Rossanna Pezo, MD

Katarzyna Jerzak, MD

Lilian Gien, MD

Stephanie Lheureux, MD

Neesha Dhani, MD

Gita Bhat, MD

Robert C. Grant, MD

Husam Ali Mahmoud Alqaisi, MD

Amit M. Oza, MD

Diane Provencher, MD

Annick Pina, MD

Beatrice Cormier, MD

Omar Moreira-Basha, MD

Thomas Warkus, MD

Vanessa Samouëlian, MD

The purpose of this Phase I study is to determine if the PARP inhibitor olaparib can be safely combined with navitoclax, an inhibitor of Bcl-2/Bcl-XL, in women with TNBC who have somatic or germline mutations in breast cancer gene one (BRCA1) and breast cancer gene two (BRCA2) BRCA1/2 or PALB2 and in women with recurrent HGSC who have progressed greater than 6 months since their last platinum containing chemotherapy. The trial is designed as an open- label multi-center Phase I interventional and translational study. It will identify the dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and RP2D of olaparib combined with navitoclax for study in Phase II. There is a plan for a follow on Phase II study depending on the results obtained during this Phase I trial.The rationale for this study is that for a subset of patients, olaparib, will increase tumor cell survival dependence on inhibition of cell death by Bcl 2/Bcl- XL. Thus, navitoclax will augment apoptosis induced by PARP inhibition with olaparib.

In this trial, olaparib will be delivered alone for 14 days with the hypothesis that priming of the apoptotic machinery will be required prior to introduction of the senolytic agent (navitoclax). To date navitoclax and olaparib have not been combined in the clinic. The Phase I study will therefore be conducted to define the recommended Phase II dose (RP2D). A plan for a future Phase II study will depend on the results obtained during this Phase I trial. Based on the potential for overlapping toxicity (particularly hematologic toxicity) an interrupted dosing schedule will be used for the navitoclax. Based on preclinical studies it is believed that intermittent delivery of the senolytic agent is in line with the proposed mechanism of action. Subsequently the dose of navitoclax will be escalated with a fixed dose of olaparib in 28-day cycles.

The trial is designed as an open-label multi-center Phase I interventional and translational study. It will identify the dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and RP2D of olaparib combined with navitoclax for study in Phase II.

Combination of Olaparib and Navitoclax in Women With HGSC and TNBC

A Phase I Trial of the Combination of Olaparib and Navitoclax in Women With High Grade Serous Epithelial Ovarian Cancer and Triple Negative Breast Cancer

The RP2D will be determined based on an evaluation of multiple endpoints, which will include the DLT( dose limiting toxicity) rate.

The maximum drug concentration will be measured in blood samples as part of the PK profile of olaparib and navitoclax when given in combination.

The time to reach maximum drug concentration will be measured in blood samples as part of the PK profile of olaparib and navitoclax when given in combination.

Exactis Innovation

Centre hospitalier de l'Université de Montréal (CHUM)

Princess Margaret Hospital, Canada

Sunnybrook Health Sciences Centre

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Chidamide Bridging for CAR-T Therapy	NCT05370547	Non Hodgkin's L...	Chidamide Fludarabine and... Anti-CD19 CAR-T...	16 Years - 75 Years	Chinese PLA General Hospital
Combination of Olaparib and Navitoclax in Women With HGSC and TNBC	NCT05358639	High Grade Sero... Triple Negative... Ovarian Cancer	Olaparib tablet Navitoclax	18 Years -	Sunnybrook Health Sciences Centre
Combination of Olaparib and Navitoclax in Women With HGSC and TNBC	NCT05358639	High Grade Sero... Triple Negative... Ovarian Cancer	Olaparib tablet Navitoclax	18 Years -	Sunnybrook Health Sciences Centre
Combination of Olaparib and Navitoclax in Women With HGSC and TNBC	NCT05358639	High Grade Sero... Triple Negative... Ovarian Cancer	Olaparib tablet Navitoclax	18 Years -	Sunnybrook Health Sciences Centre

Spots Global Cancer Trial Database for noxa

Every month we try and update this database with for noxa cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for noxa

Every month we try and update this database with for noxa cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for noxa cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.