Neoplasms

Blood and Lymph Conditions

All Conditions

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Antineoplastic Agents

All Drugs and Chemicals

Pharmaceutical Solutions

Venetoclax

Azacitidine

Antimetabolites

Enzyme Inhibitors

Unfit adult participants with AML who responded sub-optimally to at least 2 and not more than 4 cycles ( 1 cycle=28 days) of first-line venetoclax plus azacitidine therapy

Unfit adult participants with newly diagnosed AML and with adverse genetic risk stratification (according to ELN 2022)(Except TP53 mutation positive participants).

Siremadlin is a capsule taken orally once a day (QD) and comes in 10 mg, 20 mg and 30 mg strengths

siremadlin

Venetoclax is a tablet taken orally once a day (QD) and comes in 10 mg, 50 mg and 100 mg strengths.

venetoclax

Azacitidine is a powder for suspension for injection or powder for solution for infusion taken intravenously or subcutaneously according to standard local clinical practice

azacitidine

Novartis Pharmaceuticals

A study of siremadlin in combination with venetoclax plus azacitidine in adult participants with AML who are ineligible for chemotherapy.

The primary purpose of this study was to assess whether siremadlin in combination with venetoclax plus azacitidine can enhance the clinical response in unfit AML patients without unacceptable levels of treatment-emergent toxicities.

The recommended dose of siremadlin in combination with venetoclax plus azacitidine will be determined to be explored further in the expansion phase and the preliminary efficacy in achieving Complete Remission (CR) will be evaluated in participants who responded sub-optimally to first-line venetoclax plus azacitidine treatment.

The study was planned to be conducted in two parts. The primary purpose of Part 1 (Safety Run- in) was to rule out excessive toxicity of siremadlin when administered in combination with venetoclax plus azacitidine while the primary purpose of Part 2 (Expansion) was to evaluate the preliminary efficacy of siremadlin when combined with venetoclax plus azacitidine in the respective patient population.

The study treatment (siremadlin in combination with venetoclax plus azacitidine) is administered in cycles with a planned duration of 28 days and will continue until the participants experience disease progression/relapse or unacceptable toxicity.

The initial enrollment plan and safety review was as follow:

* In the Safety run-in part, 9-15 participants were planned to be enrolled in each arm. Approximately 3-6 participants were planned to be enrolled at the starting dose level of siremadlin in combination with venetoclax plus azacitidine in both arms independently. Provided the starting dose level is determined to be safe, approximately 6-9 additional participants were planned to be enrolled at dose level +1. Safety review meetings were planned to take place involving participating investigators and the Sponsor Team to make decisions regarding siremadlin dose and determine the recommended dose for expansion.
* Approximately 26 patients were planned to be treated at the recommended dose in the expansion part.

In the safety run-(Part 1) 27 sites were open for recruitment with 28 patients screened and 14 patients enrolled.

After enrolling 14 patients (6 patients in Arm 1 and 8 patients in Arm 2), Novartis took the decision to put the enrollment in permanent halt and terminate the siremadlin program. For that reason, the enrollment in Part 2 (expansion phase) will not be open. The Novartis decision was not driven by any safety concerns.

A Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Chemotherapy.

A Phase Ib/II Open Label Dose Confirmation, Proof of Concept Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Unfit Adult AML Participants Who Responded Sub-optimally to First-line Venetoclax Plus Azacitidine Treatment and in Participants With Newly Diagnosed Unfit AML Presenting With High-risk Clinical Features

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

The objective for the safety run-in is to determine the recommended dose of siremadlin in combination with venetoclax plus azacitidine to be explored further in the expansion part separately in Arm 1 and Arm 2.

The objective is to evaluate preliminary efficacy of siremadlin at the determined recommended dose for expansion (RDE) when administered in combination with venetoclax and azacitidine.

This endpoint will not be analyzed since the recommended dose was not determined due to early termination.

Assessment of CR in order to evaluate preliminary efficacy of siremadlin (in combination of venetoclax plus azacitidine) at the determined recommended dose for Arm 2 participants.

This endpoint will not be analyzed since the recommended dose was not determined due to early termination.

Assessment of duration of CR in participants who achieved a CR.

This endpoint will not be analyzed since the recommended dose was not determined due to early termination.

Assessment of CR/CRh rate and CR/CRi rate.

Assessment of duration of CR/CRh and duration of CR/CRi.

This endpoint will not be analyzed since the recommended dose was not determined due to early termination.

Assessment of Overall Survival (OS).

This endpoint will not be analyzed since the recommended dose was not determined due to early termination.

To assess rate of early mortality at 30 day and 60 days from start of study treatment

AUC0-t: The area under the concentration vs. time Curve (AUC) from time zero to specified time point.

AUClast is the AUC from time zero to the last quantifiable concentration point (last) (mass x time x volume -1).

AUCtau is the AUC to the end of the dosing interval as when possible PK samples will be collected up to 24 h postdose for siremadlin and venetoclax. Steady-state will be assumed on Day 5 (AUCtau, ss) in case of continuous dosing.

To characterize the PK of siremadlin, venetoclax and azacitidine administered in combination in each arm. Cmax is the maximum (peak) observed plasma, blood, serum or other body fluid drug concentration following drug administration (mass x volume -1)

PK parameter Tmax and concentration vs time profiles of siremadlin, venetoclax and azacitidine. Tmax is the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after drug administration (time).

To assess the effect of siremadlin in combination with venetoclax plus azacitidine in MRD

Carcinoma

thioureidobutyronitrile intravenous once/week for 3 weeks/ cycle

thioureidobutyronitrile

Geoffrey Shapiro, MD PhD

In the laboratory, Kevetrin activates p53, a tumor suppressor protein that has an important role in protecting the body. p53 functions by activating proteins that repair DNA and kill cells that have genetic mutations such as in cancers. Research experiments showed that when cancer cells were treated with Kevetrin, it activated p53 which induced p21, a protein that inhibits cancer cell growth. p53 also induced PUMA (p53 up-regulated modulator of apoptosis), a protein that causes tumor cell death. Because of these activities, slowing cancer cell growth and causing cancer cell death, Kevetrin may help to treat tumors.

Kevetrin was found to be effective in pre-clinical studies of human xenograft tumor models and was reasonably well-tolerated at therapeutic doses in the non-clinical animal studies. Kevetrin was also effective in multi-drug resistant tumor models; therefore, Kevetrin has the potential to treat tumors that have become resistant to standard chemotherapy. This trial will determine tolerance in humans and, possibly, efficacy with a Phase I, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of Kevetrin, in adult patients with solid tumors.

The primary objectives are the following:

* To determine the maximum tolerated dose (MTD) of Kevetrin.
* To determine the dose limiting toxicities (DLT) of Kevetrin.
* To establish a safe dose level of Kevetrin that can be used for future studies.

The secondary objectives are to determine the following:

* The pharmacokinetics of Kevetrin in humans.
* Observe for evidence of antitumor activity following administration of Kevetrin.
* If Kevetrin induces changes in the biomarker p21 in peripheral blood lymphocytes.
* If there is a pharmacodynamic relationship between the plasma concentrations of Kevetrin and a clinical or cellular effect.

During each 4 week cycle, each patient will receive three weekly doses of Kevetrin given as a 1 hour intravenous infusion followed by a 1 week off-treatment period. Following each dose, each patient will be monitored. If the patients have acceptable safety and tolerance, Kevetrin will be given once weekly for a total of 3 weeks. During each cycle patients will be evaluated for safety, tolerance, and Dose-Limiting Toxicity (DLT) that occur during a cycle.

A Safety, Pharmacokinetic and Pharmacodynamic Study of Kevetrin in Patients With Advanced Solid Tumors

A Phase 1, Open-Label, Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of Kevetrin (Thioureidobutyronitrile) Administered Intravenously, in Patients With Advanced Solid Tumors

A dose will be declared the MTD if at least 1 patient out of 6 patients experience a dose limiting toxicity (DLT) at the highest dose level below the maximally administered dose. Once an MTD has been established, up to 12 additional patients may be enrolled at the MTD dose level for confirmation of safety.

The maximally administered dose is if 1 or more of 6 patients experience a DLT.

The definition of dose limiting toxicity (DLT) is in accord with the NCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE). Dose limiting toxicity will be defined as:

* Grade 3 or 4 neutropenia complicated by fever, or greater than 38.5°C documented infection, or Grade 4 neutropenia of greater than 7 days duration
* Grade 4 thrombocytopenia or grade 3 thrombocytopenia complicated by hemorrhage
* Any grade greater than 3 non-hematologic toxicity unless there is clear alternative evidence that the adverse event (AE) was not caused by Kevetrin
* Grade 3 diarrhea, nausea, or vomiting may be excluded from dose-limiting toxicities provided that the maximum time limit for supportive measures is 48 hours.

The pharmacokinetics (PK) of Kevetrin will be determined for all patients enrolled in the study on Day 1 of Cycle 1 and Day 15 of Cycle 2. Blood samples will be obtained before dosing, 30 minutes after starting the infusion, 1 hr, 1 hr 10 min, 1 hr 20 min, 1 hr 30 min, 1 hr 45 min, 2 hr, 2 hr 30 min, 3 hr, 4 hr, 5 hr, 7 hr, and 24 hr after the initiation of the infusion.

The pharmacokinetic profile will be analyzed by standard noncompartmental methods to provide estimated values of the pharmacokinetic parameters and associated variables, such as area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax) of Kevetrin. Associations between pharmacokinetic variables and drug-related toxicities will be evaluated.

The pharmacokinetics (PK) of Kevetrin will be determined for all patients enrolled in the study on Day 1 of Cycle 1 and Day 15 of Cycle 2. Blood samples will be obtained before dosing, 30 minutes after starting the infusion, 1 hr, 1 hr 10 min, 1 hr 20 min, 1 hr 30 min, 1 hr 45 min, 2 hr, 2 hr 30 min, 3 hr, 4 hr, 5 hr, 7 hr, and 24 hr after the initiation of the infusion.

The pharmacokinetic profile will be analyzed by standard noncompartmental methods to provide estimated values of the pharmacokinetic parameters and associated variables, including area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax) of Kevetrin. Associations between pharmacokinetic variables and drug-related toxicities will be evaluated.

Change in tumor size based on RECIST criteria version 1.1. using MRI, CT scan, and/or standard of care imaging

A decrease in a tumor marker in the serum may also suggest evidence of anti-tumor efficacy. The following tumor markers will be evaluated: Carcinoembryonic antigen (CEA), Cancer Antigen 125 (CA125), Cancer Antigen 19-9 (CA19-9), Cancer Antigen 15-3 (CA15-3), Prostate Specific Antigen (PSA), or other appropriate markers. The choice of the individual tumor markers will be based on the type of tumor of the patient and the testing that has preceded the patient's participation in this study.

For biomarker analysis, p21 expression, assayed by qPCR, in peripheral blood lymphocytes after Kevetrin administration.

Dana-Farber Cancer Institute

Beth Israel Deaconess Medical Center

Cellceutix Corporation

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Skin and Connective Tissue Diseases

Digestive System Diseases

Gland and Hormone Related Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Uterine Cervical Neoplasms

Cholangiocarcinoma

Breast Neoplasms

Adenocarcinoma

Pancreatic Neoplasms

Melanoma

Carcinoma, Non-Small-Cell Lung

Carcinoma, Transitional Cell

Stomach Neoplasms

Sarcoma

Lung Neoplasms

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Adenocarcinoma of Lung

Adrenocortical Carcinoma

Biliary Tract Neoplasms

Neoplasms, Glandular and Epithelial

Respiratory Tract Neoplasms

Thoracic Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Biliary Tract Diseases

Endocrine Gland Neoplasms

Endocrine System Diseases

Pancreatic Diseases

Adrenal Cortex Neoplasms

Adrenal Gland Neoplasms

Adrenal Cortex Diseases

Adrenal Gland Diseases

Pancreatic Cancer

Ovarian Cancer

Transitional Cell Carcinoma

Bile Duct Cancer

Stomach Cancer

Ovarian Epithelial Cancer

Soft Tissue Sarcoma

Biliary Tract Cancer

Germ Cells Tumors

Lung Adenocarcinoma

Testicular Germ Cell Tumor

260 mg once dailly orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle

260 mg once daily orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle

RAIN-32

Phase 2, multicenter, single-arm, open-label basket study designed to evaluate the safety and efficacy of milademetan in patients with advanced or metastatic solid tumors refractory or intolerant to standard-of-care therapy that exhibit wild-type (WT) TP53 and MDM2 copy number (CN) ≥ 8 using prespecified biomarker criteria.

Approximately 65 patients will be enrolled to receive milademetan.

Patients will receive the study drug until reaching unequivocal disease progression (per Response Evaluation Criteria in Solid Tumors \[RECIST\] version \[v\]1.1), as determined by the Investigator; experiencing unmanageable toxicity; or until other treatment discontinuation criteria are met. Patients may be treated beyond tumor progression if they are experiencing clinical benefit based on the assessment of the Investigator in discussion with the Medical Monitor.

All patients will be followed for documentation of disease progression and survival information (i.e., date and cause of death). Long-term follow-up will continue every 12 weeks (± 7 days) until the endpoint of death, the patient is lost to follow-up, or for 24 months following the final dose of the study drug, whichever comes first.

Milademetan in Advanced/Metastatic Solid Tumors

A Phase 2 Basket Study of Milademetan in Advanced/Metastatic Solid Tumors (MANTRA-2)

DOR defined as the time from the date of first documentation of CR or PR according to RECIST v1.1 to the date of disease progression or death due to any cause according to Investigator assessment

PFS defined as the time from the date of the first dose of the study drug to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause according to Investigator assessment

GMI defined as the ratio of Time to Progression (TTP) with the nth line of therapy (TTPn; here defined as milademetan) to the most recent prior line of therapy (TTPn-1)

DCR defined as the percentage of patients with confirmed CR, PR, or stable disease (SD) for ≥ 16 weeks

OS as measured from the date of the first dose of the study drug until the date of death due to any cause

Rain Oncology Inc

Liposarcoma

Neoplasms, Adipose Tissue

Neoplasms, Connective and Soft Tissue

Trabectedin

Antineoplastic Agents, Alkylating

Alkylating Agents

260 mg once daily orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle.

1.5 mg/m2 body surface area as a 24-hour IV infusion, every 3 weeks.

1.5 mg/m2 body surface area as a 24-hour IV infusion, every 3 weeks

Randomized, multicenter, open-label, Phase 3 registration study designed to evaluate the safety and efficacy of milademetan compared to trabectedin in patients with unresectable (i.e., where resection is deemed to cause unacceptable morbidity or mortality) or metastatic DD liposarcoma that progressed on 1 or more prior systemic therapies, including at least 1 anthracycline-based therapy.

Approximately 160 patients will be randomly assigned in a 1:1 ratio to receive milademetan or trabectedin. Randomization will be stratified by the ECOG performance status (0 or 1) and number of prior treatments (≤ 2 or \> 2) for the patient's liposarcoma.

Patients will receive study drug (i.e., milademetan or trabectedin) until reaching unequivocal disease progression (RECIST v.1.1) as determined by the Investigator, experiencing unmanageable toxicity, or until other treatment discontinuation criteria are met. Patients may be treated beyond tumor progression if they are experiencing clinical benefit based on the assessment of the Investigator in discussion with the Medical Monitor. All patients will be followed for documentation of disease progression and survival information (i.e., date and cause of death) and subsequent treatment information (i.e., date/duration of treatment, response, and subsequent disease progression). Long-term follow-up will continue every 12 weeks (± 7 days) until the endpoint of death, the patient is lost to follow-up, or for 24 months following the final dose of study drug, whichever comes first.

Treatment of Milademetan Versus Trabectedin in Patient With Dedifferentiated Liposarcoma

A Randomized Multicenter Phase 3 Study of Milademetan Versus Trabectedin in Patients With Dedifferentiated Liposarcoma

OS as measured from the date of randomization to date of death by any cause

DCR defined as the percentage of patients who have achieved CR, PR, or SD for ≥ 8 weeks

ORR defined as the percentage of patients who achieve a confirmed CR or PR

DOR defined as the time from date of first response to date of disease progression or death

PFS defined as the time from randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause, based on Investigator assessments

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Chemotherapy.	NCT05155709	Acute Myeloid L...	siremadlin venetoclax azacitidine	18 Years - 99 Years	Novartis
A Safety, Pharmacokinetic and Pharmacodynamic Study of Kevetrin in Patients With Advanced Solid Tumors	NCT01664000	Solid Tumors	thioureidobutyr...	18 Years -	Cellceutix Corporation
Milademetan in Advanced/Metastatic Solid Tumors	NCT05012397	Solid Tumors Head and Neck C... Cholangiocarcin... Sarcoma Lung Adenocarci... Bladder Urothel... Stomach Adenoca... Breast Cancer I... Ovarian Carcino... Cervical Cancer Non Small Cell ... Gastric Cancer Biliary Tract C... Melanoma Pancreas Cancer MDM2 Gene Ampli... Testicular Germ... Adrenocortical ...	RAIN-32	18 Years -	Rain Oncology Inc
Treatment of Milademetan Versus Trabectedin in Patient With Dedifferentiated Liposarcoma	NCT04979442	Dedifferentiate...	RAIN-32 Trabectedin	18 Years -	Rain Oncology Inc

Spots Global Cancer Trial Database for mdm2

Every month we try and update this database with for mdm2 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 mdm2

Every month we try and update this database with for mdm2 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 mdm2 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.