Neoplasms

All Conditions

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

Skin and Connective Tissue Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

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

Neoplasms by Histologic Type

Adenocarcinoma

Neoplasms, Cystic, Mucinous, and Serous

Ovarian Cancer

Ovarian Epithelial Cancer

Adenocarcinoma of the Appendix

Antineoplastic Agents

All Drugs and Chemicals

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

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Anti-Infective Agents

Amino Acids

Sirolimus

Neratinib

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Immunosuppressive Agents

Immunologic Factors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Tyrosine Kinase Inhibitors

Tyrosine

240 mg once daily with food, continuously in 21 day cycles

240 mg neratinib plus 8 mg temsirolimus IV with optional dose escalation to 15 mg temsirolimus

neratinib

temsirolimus

Clinical Development Senior Vice President

This is a Phase 2, therapeutic-exploratory, adaptive design, open-label, multicenter, multinational study evaluating neratinib monotherapy and neratinib plus temsirolimus combination therapy in patients with non-small cell lung cancer (NSCLC) who have documented somatic HER2 mutations.

This is a Phase 2, therapeutic-exploratory, adaptive design, open-label, multicenter, multinational study evaluating neratinib monotherapy and neratinib plus temsirolimus combination therapy in patients with NSCLC and documented somatic HER2 mutations. Patients randomized at study entry into 1 of 2 treatment arms:

* Arm A: neratinib 240 mg orally once daily
* Arm B: neratinib 240 mg orally once daily plus temsirolimus 8 mg once weekly by intravenous (IV) infusion

In the case of disease progression, patients initially assigned to neratinib monotherapy arm given option to add temsirolimus 8 mg IV once weekly.

Patients on combination therapy given option to dose-escalate temsirolimus to 15 mg/week at the end of first cycle of treatment, if well tolerated and at the physician's discretion. If neratinib 240 mg/day plus temsirolimus 15 mg/week dose not well tolerated, patient subsequently dose reduced back to neratinib 240 mg/day plus temsirolimus 8 mg/week.

Dosing continuous on nominal 3-week cycles until evidence of progressive disease, unacceptable toxicity, or patient withdrawal of consent.

Disease measured radiographically at baseline and every 6 weeks until disease progression or withdrawal from the study.

Neratinib With and Without Temsirolimus for Patients With HER2 Activating Mutations in Non-Small Cell Lung Cancer

A Phase 2 Study of Neratinib and Neratinib Plus Temsirolimus in Patients With Non-Small Cell Lung Cancer Carrying Known HER2 Activating Mutations

ORR is defined as proportion of subjects who achieved confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

A complete or partial response must be confirmed no less than 4-weeks after the criteria for response are initially met.

CBR is defined as the proportion of patients who achieved objective response (CR or PR) or stable disease (SD) for at least 12 weeks.

Measured from the time at which measurement criteria were first met for CR or PR (whichever status was recorded first), until the date of first recurrence, progressive disease (PD), or death was objectively documented, taking as a reference for PD the smallest measurements recorded since enrollment, per RECIST (v1.1) criteria.

Defined as time from date of randomization until the first disease recurrence or progression per RECIST V1.1 or death due to any cause; censored at the last assessable evaluation or at the initiation of new anti-cancer therapy. Disease assessment is based on investigator tumor assessments. If no post-baseline tumor assessment then censored at enrollment date.

Defined as the time (month) from randomization to death due to any cause; censored at the date last known alive.

Puma Biotechnology, Inc.

Neratinib+Temsirolimus

Neratinib 240 mg + Temsirolimus 15 mg for subjects who crossed over from Neratinb 240 mg arm

Ner+Tem Post Crossover

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

All subjects who received at least one dose of study medication

Senior Director, Clinical Operations

All subjects who received at least 1 dose of drug

Objective Response Rate (ORR)

All subjects who received at least one dose.

Clinical Benefit Rate (CBR)

Less than 3 months

3 to less than 6 months

6 to less than 12 months

Greater than 12 months

All subjects who received at least 1 dose of drug and had either complete or partial response.

Duration of Response (DOR)

Progression Free Survival (PFS)

Overall Survival (OS)

Overall Study

Digestive System Diseases

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Trastuzumab

Cetuximab

Antineoplastic Agents, Immunological

Guardant360 test on blood from select patients with known HER2 status.

Prior to assignment to Arm 1, HER2 test on blood obtained from Quadruple Wild-Type patients who received anti-EGFR therapy. Patients with HER2 amplified, HER2 Wild-Type or HER2 mutated will recieve:

• Neratinib daily + Trastuzumab weekly until disease progression

Patients with HER2 Wild Type or HER2 amplified with no prior anti-EGFR therapy will receive:

• Neratinib daily + Cetuximab weekly until disease progression

Patients with HER2 amplified tumors with prior anti-EGFR therapy and/or HER2 mutated colorectal cancer with/or without prior anti-EGFR therapy will receive 4 mg/kg IV loading dose; then 2 mg/kg IV weekly until disease progression. Neratinib: 240 mg taken by mouth daily until disease progression.

Patients with HER2 WT or HER2 amplified with no prior anti-EGFR therapy: 400 mg/m2 IV loading dose; then 250 mg/m2 IV weekly. Neratinib 240 mg taken by mouth daily until disease progression.

240 mg taken by mouth daily until disease progression.

Prior to assignment to Arm 1, the Guardant360 diagnostic test will be conducted in blood to confirm known HER2 status for select patients.

Guardant360 Diagnostic Test

Norman Wolmark, MD

This is a phase II trial to examine the efficacy of neratinib plus trastuzumab or neratinib plus cetuximab in patients with "quadruple wild-type" (all RAS/NRAS/BRAF/PIK3CA wild-type), metastatic colorectal cancer based on HER2 status (amplified, non-amplified \[wild-type\] or mutated). Patients must have confirmed quadruple wild-type (WT) genotype, via NSABP MPR-1 or from colonic biopsy or a metastatic biopsy taken prior to treatment, and known HER2 status.

The primary aim of this study is to determine the progression-free survival (PFS) in each of these HER2 populations. Secondary aims include overall response rate (ORR) and clinical benefit rate (CBR) defined as the objective tumor decrease and stable disease by RECIST 1.1 criteria; toxicity and safety profile. Exploratory analysis will be performed to assess for molecular predictors of response. The local site will make the primary determination of response and progression based on all radiographic images (e.g., MRI, CT, PET, bone scan, etc.) as well as other relevant reports documenting disease response or progression.

For patients identified as quadruple WT with prior cetuximab or panitumumab treatment, a pre-entry blood sample will be required from consenting patients to confirm HER2 amplification for study eligibility.

Patients with quadruple WT, HER2 amplified with prior anti-EGRF therapy and/or HER2 mutated colorectal cancer with/or without prior anti-EGRF therapy will receive concurrent therapy with trastuzumab 4 mg/kg IV loading dose followed by 2 mg/kg IV weekly and neratinib 240 mg taken by mouth daily until disease progression, (Arm 1).

Patients with quadruple WT, HER2 WT or HER2 amplified with no prior anti-EGRF therapy will be assigned to receive concurrent therapy with cetuximab (400 mg/m2 IV loading dose followed by 250 mg/m2 IV weekly), and neratinib 240 mg taken by mouth daily until disease progression (Arm 2).

Approximately thirty-five (35) patients will be accrued to this study; 15 patients with HER2 amplified, 15 patients with HER2 WT, and approximately 5 patients with HER2 mutated colorectal cancer. Patients with HER2 WT or HER2 amplified mCRC who drop out of the study before the first scan (for whatever reason) will be replaced. Patients who drop out of the study after the first scan but before the second scan will be considered to have progressive disease.

Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).

Required blood and tissue samples will be collected at entry into the study. A tumor biopsy will be procured from an accessible site of metastasis before study therapy is initiated (after the patient has signed the consent form and has been screened for eligibility). Tissue will be sent to Champions Oncology Laboratory for engraftment into an NOD/SCID mouse to develop a patient-derived xenograft (PDX) model, and to NSABP Pathology Division for correlative science. Tissue samples from PDX models will be sent to Celcuity for functional HER2 signaling assay. Additional blood samples will be collected during the course of treatment.

Optional tumor and blood samples will be collected from consenting patients at the time of disease progression.

Study of Neratinib +Trastuzumab or Neratinib + Cetuximab in Patients With KRAS/NRAS/BRAF/PIK3CA Wild-Type Metastatic Colorectal Cancer by HER2 Status

A Phase II Study Evaluating the Combination of Neratinib Plus Trastuzumab or Neratinib Plus Cetuximab in Patients With "Quadruple Wild-Type" (KRAS/NRAS/BRAF/PIK3CA Wild-Type) Metastatic Colorectal Cancer Based on HER2 Status: Amplified, Non-Amplified (Wild-Type) or Mutated

Progression free survival (PFS). Percentage of patients alive with absence of progression assessed using RECIST 1.1 criteria.

Progression free survival (PFS). Percentage of patients alive with absence of progression assessed using RECIST 1.1 criteria

Rate of best overall response using measurement of tumor in patients with measurable metastatic disease

Rate of disease status by continuous tumor measurement.

Frequency of adverse events categorized using the NCI Common Terminology Criteria for Adverse Events version 4.0.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Safety, Pharmacokinetic and Pharmacodynamic Study of Kevetrin in Patients With Advanced Solid Tumors	NCT01664000	Solid Tumors	thioureidobutyr...	18 Years -	Cellceutix Corporation
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
Neratinib With and Without Temsirolimus for Patients With HER2 Activating Mutations in Non-Small Cell Lung Cancer	NCT01827267	HER2-mutant Non...	neratinib temsirolimus	18 Years -	Puma Biotechnology, Inc.
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
Study of Neratinib +Trastuzumab or Neratinib + Cetuximab in Patients With KRAS/NRAS/BRAF/PIK3CA Wild-Type Metastatic Colorectal Cancer by HER2 Status	NCT03457896	Metastatic Colo...	Trastuzumab Cetuximab Neratinib Guardant360 Dia...	18 Years -	NSABP Foundation Inc
Study of Neratinib +Trastuzumab or Neratinib + Cetuximab in Patients With KRAS/NRAS/BRAF/PIK3CA Wild-Type Metastatic Colorectal Cancer by HER2 Status	NCT03457896	Metastatic Colo...	Trastuzumab Cetuximab Neratinib Guardant360 Dia...	18 Years -	NSABP Foundation Inc
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 puma

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

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