Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Each subject receive BCMA CAR T-cells by intravenous infusion

BCMA CAR-T cells

He Huang, MD

Mingming Zhang, MD

Clinical Trial for the Safety and Efficacy of BCMA CAR-T Cell Therapy for Newly Diagnosed Multiple Myeloma

This is a single arm, open-label, single-center study. This study is indicated for newly diagnosed multiple myeloma. The selections of dose levels and the number of subjects are based on clinical trials of similar foreign products. 40 patients will be enrolled. Primary objective is to explore the safety and efficacy

A Study of BCMA CAR-T Cell Therapy for Newly Diagnosed Multiple Myeloma

Adverse events assessed according to NCI-CTCAE v5.0 criteria

Incidence of treatment-emergent adverse events \[Safety and Tolerability\]

Assessment of ORR (ORR = sCR+CR+VGPR+PR+MR) at Month 6, 12, 18 and 24

Proportion of subjects who achieved morphological complete response (CR) and complete response with hematologic incomplete recovery (CRi)

Proportion of subjects who achieved a partial response (PR)

Death from any cause from the beginning of cell transfusion

Yake Biotechnology Ltd.

Zhejiang University

Clinical Professor

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

All Drugs and Chemicals

Dexamethasone

Immunomodulating Agents

Lenalidomide

Dexamethasone acetate

Proteasome Inhibitors

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Immunologic Factors

Angiogenesis Inhibitors

Growth Inhibitors

Carfilzomib (K):

* 20 mg/m2 IV on day 1 of cycle 1;
* 56 mg/m2 IV on days 8 and 15 in cycle 1;
* 56 mg/m2 IV on days 1, 8 and 15 in cycles 2-12;
* 56 mg/m2 on days 1 and 15 from cycle 13 and onwards.

Lenalidomide (R):

- 25 mg orally on days 1-21 of each cycle.

Dexamethasone (d):

- 40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is a 28-day cycle.

Until PD or intolerance. Only patients that achieve at least a VGPR within the first year of treatment and in sustained MRD negativity (MRD negative at least at 10-5 after 1 and 2 years of therapy) will stop carfilzomib after 2 years of treatment, and will continue with lenalidomide and dexamethasone administration.

Lenalidomide (R):

-25 mg orally on days 1-21 of each cycle.

Dexamethasone (d):

-40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is a 28-day cycles.

Until PD or intolerance.

* 20 mg/m2 IV on day 1 of cycle 1 enhanced to 56 mg/m2 on days 8, and 15 of cycle 1;
* 56 mg/m2 IV on days 1, 8 and 15 in cycles 2-12;
* 56 mg/m2 IV on days 1 and 15 from cycle 13 and onwards.

Carfilzomib

- 25 mg orally on days 1-21 of each cycle.

- 40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is to be repeated every 28 days. Patients that achieve at least a VGPR within the first year of study treatment and in sustained MRD negativity (MRD negative at least at 10-5 after 1 and 2 years of therapy) will stop carfilzomib administration after 2 years and will continue with lenalidomide and dexamethasone treatment until disease progression or intolerance to the therapy. Other patients will continue carfilzomib administration until disease progression or intolerance.

For patients \>75 years of age, the dose of dexamethasone is 20 mg/day on Days 1, 8, 15 and 22 of each treatment cycle.

Sara Bringhen

The combination of lenalidomide plus low-dose dexamethasone (Rd) is considered the new standard for elderly newly diagnosed multiple myeloma (NDMM) patients. The combination carfilzomib plus lenalidomide-dexamethasone (KRd) in relapsed-refractory MM patients improved the progression-free survival (PFS) of approximately 1 year compared to standard Rd treatment. In a small phase 2 trial (23 pts) the KRd combination in elderly NDMM pts showed a complete response (CR) rate of 79% and a PFS at 3 years of 80%. Cardiovascular adverse events are the most limiting toxicities, especially in elderly patients.

This protocol is a randomized, multicenter study designed to determine the MRD negativity and the PFS of KRd treatment regimen.

Patients will be randomized in a 1:1 ratio to receive carfilzomib-lenalidomide-dexamethasone (KRd - Arm A) or lenalidomide-dexamethasone (Rd - Arm B).

Patients will be stratified basing on international staging system (ISS) and fitness status using a web-based procedure completely concealed to study participants.

All consecutive patients ≥ 65 years with newly diagnosed MM will be enrolled in a large randomized study during a period of 24 months.

Patients will be treated until disease progression or intolerance to the therapy. The only exception is for patients enrolled in KRd arm who achieve at least a VGPR during the first year of treatment and in sustained MRD negativity (MRD negative at least at 10-5 after one and two years of therapy): these patients will stop carfilzomib administration after 2 years, whereas treatment with lenalidomide and dexamethasone will be continued.

A Trial That Compare Two Treatments in Newly Diagnosed Myeloma Patients Not Eligible for Transplant

Carfilzomib - Lenalidmide - Dexamethasone (KRd) Versus Lenalidomi - Dexamethasone (Rd) in Newly Diagnosed Myeloma Patients Not Eligible for Autologous Stem Cell Transplantation: a Randomized Phas III Trial

1. Minimal residual disease (MRD): unit of measure is not applicable, MRD is expressed as a pure number

2. Progression-free survival (PFS): unit of measure is not applicable, PFS is expressed as a pure number

Incidence of dose reduction and drug discontinuation in both treatment arms.

Benefit of proper cardiovascular baseline assessment and monitoring during treatment in both treatment arms:to mitigate major cardiovascular adverse event incidence, to prolong duration of treatment, to improve efficacy.

Safety as rate of dose reduction, drug discontinuation and toxicities

Response rate will include complete response (CR), very good partial response (VGPR) and partial response (PR) using the International Response Criteria. Responders are defined as subjects with at least a PR.

Time from randomization to objective tumor progression on next-line treatment or death from any cause.

Time to progression will be measured from the date of randomization to the date of first observation of PD, or deaths related to PD.

Time between first documentation of response and PD. Responders without disease progression will be censored either at the time of lost to FU, at the time of death due to other cause than PD, or at the end of the study.

Time between randomization and death. Subjects who die will be censored at time of death as an event, regardless cause of death.

Time to next therapy will be measured from the date of randomization to the date of next anti-myeloma therapy. Death due to any cause before starting therapy will be considered an event.

Correlation between MRD negativity and PFS, PFS2, TTP, TNT and OS

The following outcomes will be analysed in subgroups with different prognostic factors:

* Progression-free survival (PFS),
* Time to second disease progression (PFS2),
* Time to progression (TTP),
* Time to next therapy (TNT ),
* Overall survival (OS)

Fondazione EMN Italy Onlus

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Anti-Infective Agents

Respiratory System Agents

Acetylcysteine

N-monoacetylcystine

Antiviral Agents

Expectorants

Antioxidants

Protective Agents

Antidotes

NSC-CRAd-S-pk7 1·50 x 10⁸ NSCs loaded with1·875 x viral particles administered intra-tumorally on Day 0 and Day 15, then every 4 weeks for up to 6 total doses.

NSC-CRAd-S-pk7 1·50 x 10⁸ NSCs loaded with 1·875 x viral particles administered intra-tumorally on Day 0 and Day 15, then every 4 weeks for up to 6 total doses. In addition, N-acetylcysteine amide (NACA) 600 mg oral, is taken daily from registration to just prior to dose 2 of NSC-CRAd-S-pk7.

NSC-CRAd-S-pk7

N-acetylcysteine amide (NACA) 600 mg oral, is taken daily from registration to just prior to dose 2 of NSC-CRAd-S-pk7.

N-acetylcysteine amide (NACA)

Christina Amidei, PhD

Roger Stupp, MD

The goal of this clinical trial is to learn about the safety and feasibility of administering repeated doses of neural stem cell (NSC)-conditionally replicative adenovirus (CRAd)-survivin (S)-protomer (p)k7, in persons with newly diagnosed high grade glioma.

The main questions it aims to answer are:

* whether multiple doses of NSC-CRAd-S-pk7 are safe and feasible
* how multiple doses of NSC-CRAd-S-pk7 influence tumor response, overall survival, time to tumor progression, and quality of life.

Participants will:

* undergo a biopsy to confirm high grade glioma, then receive the first dose of NSC-CRAd-S-pk7 into the brain
* about 2 weeks later, undergo surgery to remove the tumor and receive the second dose of NSC-CRAd-S-pk7 into the brain
* start chemoradiation about 2 weeks after surgery, then about 2 weeks later, receive the 3rd dose of NSC-CRAd-S-pk7 into the brain
* four weeks later, at the end of chemoradiation, receive a fourth dose of NSC-CRAd-S-pk7 into the brain.
* after radiation is finished, receive standard of care chemotherapy and tumor-treating fields. Two additional doses of NSC-CRAd-S-pk7 will be given every 4 weeks.

Every other patient enrolled will receive N-acetylcysteine amide (NACA), from registration until the day prior to surgery and the second dose of NSC-CRAd-S-pk7.

The treatment regimen contains 3 phases:

Surgical phase:

Patients undergo a biopsy and upon intraoperative confirmation of high grade glioma, NSC-CRAd-S-pk7 dose #1 will be injected into the biopsy site. Patients will undergo resection of the tumor 14 (+/- 3) days later, administration of second dose of the investigational product (NSC-CRAd-S-pk7 dose #2), and implantation of the catheter system. The investigational product will then be given monthly for a total of 6 doses (see below).

Every other patient enrolled (beginning with the first patient) will also undergo oral administration of NACA (an over-the-counter drug that acts as a free radical scavenger and improves NSC viability) starting at registration until the day prior to surgical tumor resection and planned investigational product injection #2.

Radiotherapy phase:

After recovery from surgery (usually within 2 weeks), standard chemoradiotherapy will be initiated consisting of daily radiotherapy (2 Gy per fraction x 30 fractions) and concomitant temozolomide (TMZ) chemotherapy (75 mg/m2 daily from day 1 of RT until last day of RT).

About 10-14 days into radiotherapy (= approx. 4 weeks after intraoperative dose #2), patients will be receiving NSC-CRAd-S-pk7 dose #3 through the previously implanted catheter system. This also marks the beginning of the formal dose-limiting toxicity (DLT) period, as this virus' survivin gene promoter is activated by the concomitant irradiation.

Four weeks later, ie. at the end of radiotherapy dose #4 is administered as previously, provided no DLT toxicity has been observed and viral treatment related toxicities have returned to grade ≤ 2.

Adjuvant (also called maintenance) phase:

As per standard of care, approx. 4 weeks after end of radiotherapy, patients will start maintenance TMZ chemotherapy (150 - 200 mg/m2, daily x 5 every 28 days) and loco-regional treatment with alternating Tumor Treating Fields (TTFields, Optune®). NSC-CRAd-S-pk7 doses #5 and #6 will be administered concurrently (± 3 days) with adjuvant cycle 1 and 2 of TMZ.

Both groups will receive up to 6 doses of NSC-CRAd-S-pk7 in addition to standard of care radiation and temozolomide. Every other patient enrolled (beginning with the first patient) will undergo oral administration of N-acetylcysteine amide (NACA).

Repeated Neural Stem Cell Based Virotherapy for Newly Diagnosed High Grade Glioma

A Phase I Study of Repeated Neural Stem Cell Based Virotherapy in Combination With N-Acetylcysteine Amid (NACA) and Standard Radiation and Chemotherapy for Newly Diagnosed High Grade Glioma

No individual participant data (IPD) will be shared with other researchers.

Change in score on FACT-Br over time as a measure of quality of life, with scores ranging from 0-200; higher scores indicate better quality of life.

Determination of the dose limiting toxicity of repeated dosing of NSC-CRAd-S-pk7

Objective response to therapy as determined by Immune Response Assessment in Neuro-Oncology (iRANO) criteria

Overall survival time from the first study product injection to death

Time from the first study product injection to first confirmed disease progression as determined by objective tumor response

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of BCMA CAR-T Cell Therapy for Newly Diagnosed Multiple Myeloma	NCT05712083	Multiple Myelom... New Diagnosis T...	BCMA CAR-T cell...	-	Zhejiang University
A Trial That Compare Two Treatments in Newly Diagnosed Myeloma Patients Not Eligible for Transplant	NCT04096066	Multiple Myelom... New Diagnosis T...	Carfilzomib Lenalidomide Dexamethasone	65 Years -	Fondazione EMN Italy Onlus
Repeated Neural Stem Cell Based Virotherapy for Newly Diagnosed High Grade Glioma	NCT06169280	Glioma, Maligna... New Diagnosis T...	NSC-CRAd-S-pk7 N-acetylcystein...	18 Years -	Northwestern University
A Trial That Compare Two Treatments in Newly Diagnosed Myeloma Patients Not Eligible for Transplant	NCT04096066	Multiple Myelom... New Diagnosis T...	Carfilzomib Lenalidomide Dexamethasone	65 Years -	Fondazione EMN Italy Onlus
Repeated Neural Stem Cell Based Virotherapy for Newly Diagnosed High Grade Glioma	NCT06169280	Glioma, Maligna... New Diagnosis T...	NSC-CRAd-S-pk7 N-acetylcystein...	18 Years -	Northwestern University

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