Neoplasms

Digestive System Diseases

All Conditions

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Irinotecan

Panitumumab

Topoisomerase I Inhibitors

Enzyme Inhibitors

Antineoplastic Agents, Immunological

Glutamine

Patients receive glutaminase inhibitor CB-839 PO BID on days 1-28, panitumumab IV over 60-90 minutes on days 1 and 15, and irinotecan hydrochloride IV over 90 minutes on day 1 and 15 (Phase I only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Glutaminase Inhibitor CB-839

Irinotecan Hydrochloride (phase I only)

Laboratory Biomarker Analysis

Pharmacological Study

During phase II at baseline and day 28 of cycle 1

Imaging with 11C-Glutamine PET/CT scans and 18F-FSPG PET/CT scans

Jordan Berlin, MD

This phase I/II trial studies the best dose and side effects of glutaminase inhibitor CB-839 and how well it works with panitumumab and irinotecan hydrochloride (phase I only) in treating patients with RAS wildtype colorectal cancer that has spread to other places in the body and does not respond to treatment. Glutaminase inhibitor CB-839 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as panitumumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving glutaminase inhibitor CB-839 with panitumumab and irinotecan hydrochloride may work better in treating patients with colorectal cancer.

Objectives:

Primary Objective of Phase I:

• Determine the safety and tolerability of CB-839 in combination with panitumumab and irinotecan.

Exploratory Objective of Phase I (Optional Imaging Sub-study):

• Correlate radiological features of pre- and post-treatment 11C-Glutamine PET/CT and 18F-FSPG PET/CT with clinical outcome.

Primary Objective of Phase II:

• Determine the efficacy of CB-839 in combination with panitumumab as measured by the response rate (RR).

Secondary Objectives of Phase II:

* Determine the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
* Perform the following correlative studies (in the phase 2 component):
* Correlate radiological features of pre- and post-treatment 18F-FSPG PET/CT with clinical outcome and biological correlates (tissue gene signature, exosomes).
* Collect blood samples during each radiotracer injection to assess pharmacokinetics.
* Collect pre-treatment biopsy tissue and prospectively correlate clinical outcome with a glutamine metabolism gene signature.
* Quantify exosomal content in the plasma.

Exploratory Objective of Phase II:

• Development of patient-derived organoids from pre-treatment tissue biopsy

OUTLINE: Phase I is a dose-escalation study of glutaminase inhibitor CB-839 in combination with standard doses of panitumumab and irinotecan hydrochloride. Phase II will study efficacy of glutaminase inhibitor CB-839 in combination with standard doses of panitumumab.

Patients receive glutaminase inhibitor CB-839 orally (PO) twice daily (BID) on days 1-28, panitumumab intravenously (IV) over 60-90 minutes on days 1 and 15, and irinotecan hydrochloride IV over 90 minutes on day 1 and 15 (Phase I only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 28 days and then every 3 months for up to 1 year.

Novel PET/CT Imaging Biomarkers of CB-839 in Combination With Panitumumab and Irinotecan in Patients With Metastatic and Refractory RAS Wildtype Colorectal Cancer

Phase I/II Study to Evaluate the Safety, Efficacy, and Novel PET/CT Imaging Biomarkers of CB-839 in Combination With Panitumumab and Irinotecan in Patients With Metastatic and Refractory RAS Wildtype Colorectal Cancer

The maximum tolerated dose will be determined

Will use Simon's optimal 2-stage design to monitor efficacy in this trial.

The recommended phase 2 dose will be determined.

The disease control rate will be evaluated.

evaluate the relationship between 18F-FSPG uptake at baseline and change in tumor size at the time of objective response assessment using a standard linear regression analysis. The slope will describe the shape of the relationship between SUVmax and change in tumor size, while the coefficient of determination (R2) describes the strength of the relationship between the two measures. A similar linear regression analysis will be conducted to quantify the relationship between the change in SUVmax as measured from baseline to after one cycle of therapy and change in tumor size.

Plasma exosomal content will be assessed at pre-treatment, after one cycle of treatment, and at disease progression.

will use Cox proportional hazards model to estimate the association between PET SUVmax and OS.

National Cancer Institute (NCI)

Calithera Biosciences, Inc

Vanderbilt-Ingram Cancer Center

Principal Investigator

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Skin and Connective Tissue Diseases

Gland and Hormone Related Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Uterine Cervical Neoplasms

Carcinoma

Breast Neoplasms

Triple Negative Breast Neoplasms

Pancreatic Neoplasms

Melanoma

Carcinoma, Non-Small-Cell Lung

Prostatic Neoplasms

Stomach Neoplasms

Carcinoma, Squamous Cell

Head and Neck Neoplasms

Lung Neoplasms

Carcinoma, Hepatocellular

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Urinary Bladder Neoplasms

Endometrial Neoplasms

Neoplasms, Squamous Cell

Urogenital Neoplasms

Genital Diseases

Urogenital Diseases

Neoplasms by Histologic Type

Skin Diseases

Neoplasms, Glandular and Epithelial

Genital Diseases, Female

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Uterine Neoplasms

Uterine Diseases

Breast Diseases

Esophageal Cancer

Pancreatic Cancer

Ovarian Cancer

Stomach Cancer

Ovarian Epithelial Cancer

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Groups of patients will receive increasing doses of HMBD-001 as a single agent to find a safe dose that best targets cancer cells. Approximately 26 patients with tumours known to express HER3 will be entered into this arm.

An expansion cohort of up to 25 patients with a confirmed HER3 positive or confirmed NRG1 fusion rearrangement RAS wild type colorectal cancer, castration resistant prostate cancer, triple negative breast cancer or squamous cell head and neck cancer will receive the HMBD-001 single agent RP2D as determined in Part A Arm 1.

Intravenous infusion given over a 21 or 28 day cycle dependent on dosing frequency. Number of cycles: 6 or until disease progression or unacceptable toxicity develops.

HMBD-001

Johann de Bono, Prof

Simon Lord, Dr

Derek Paisley

Johaan de Bono, Prof

This clinical trial is evaluating a drug called HMBD-001 (an anti-HER3 monoclonal antibody) in patients with advanced HER3 positive solid tumours. The main aims are to find out the maximum dose of HMBD-001 that can be given safely to patients alone and in combination with other anti-cancer agents, more about the potential side effects of HMBD-001 and how these can be treated and what happens to HMBD-001 inside the body and how it affects cancer cells.

HMBD-001 is a type of drug called a monoclonal antibody, which works by targeting a protein called HER3, that is found in high numbers in some types of cancers including those which contain NRG1 gene fusions. By attaching itself to this protein it may then work to kill the cancer cells or to stop them growing.

This is a first-in-human clinical trial which has two parts:

Part A is a 'dose escalation' phase where small groups of patients will receive increasing doses of HMBD-001 to find the safest dose which best targets cancer cells.

* In Arm 1, patients will receive HMBD-001 on its own (as a single agent).
* In Arm 2, patients will receive HMBD-001 given with other anti-cancer drugs (in combination).

Part B is a 'dose expansion' phase where larger groups of patients with specific cancer types, known to have high levels of the protein HER3 or a confirmed NRG1 gene fusion will receive the highest doses of HMBD-001 considered to be safe in Part A either alone as single agent or in combination with other anti-cancer drugs.

The main aims of the clinical trial are to find out:

* The highest dose of HMBD-001 alone and in combination with other anti-cancer drugs that can be given safely to patients.
* More about the potential side effects of HMBD-001 when given alone and in combination with other anti-cancer agents and how they can be managed.
* What happens to HMBD-001 inside the body and how it affects cancer cells.
* The potential anti-tumour activity of HMBD-001 as a single agent and in various combination regimens in specific tumour types of HER3 expressing tumours or tumours with NRG1 gene fusions.

HMBD-001 in Advanced HER3 Positive Solid Tumours

HMBD-001 (an Anti-HER3 Monoclonal Antibody) Given Intravenously as a Single Agent and in Combination in Patients With Advanced HER3 Positive Solid Tumours

Recommended dose of HMBD-001 given a) as a single agent and b) in combination with selected anticancer agent(s) with an estimated Dose Limiting Toxicity (DLT) rate that is closest to 25% using a one-stage Bayesian Continual Reassessment Method (CRM)

Number of grade 3, 4 and adverse events related to HMBD-001 given a) as a single agent and b) in combination with selected anti-cancer agent(s) graded according to National Cancer Institute Common Criteria for Adverse Events (NCI CTCAE) Version 5.0

Number of patients achieving a complete response (CR) or partial response (PR) to HMBD-001 based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 in the chosen tumour types

Maximum observed plasma concentration (Cmax) of HMBD-001

Terminal elimination half-life (t½) of HMBD-001

Time taken to reach maximum observed concentration (Tmax) of HMBD-001

Volume of distribution of HMBD-001 in plasma

Number of patients achieving a complete response (CR), partial response (PR) or stable disease (SD) based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1

Number of Patients whose cancer has not progressed at 12 and 24 months

Number of patients who are still alive at 12 and 24 months

Hummingbird Bioscience

Cancer Research UK

Symptoms and General Pathology

Neoplasm Metastasis

Neoplastic Processes

Micronutrients

Hematinics

Vitamins

Oxaliplatin

Bevacizumab

Leucovorin

Fluorouracil

Cetuximab

Levoleucovorin

Liver Extracts

Angiogenesis Inhibitors

Growth Inhibitors

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Folinic Acid

5 mg/kg intravenously administered over 90 minutes (can be reduced to 30 minutes at the minimum) on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.

250 mg/m2 intravenously administered over 60 minutes (400 mg/m2 over 120 minutes as the initial dose) on day 1 and day 8 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.

85 mg/m2 intravenously administered over 120 minutes on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.

L-OHP

200 mg/m2 intravenously administered over 120 minutes on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.

l-LV

400 mg/m2 intravenous bolus on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.

5-FU

2400 mg/m2 continuous infusion over 46 hours on day 1 and 2 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.

Yoshihiko Maehara, MD,PhD,FACS

Naohiro Tomita, MD, PhD

Ichinosuke Hyodo, MD, PhD

Michiaki Unno, MD, PhD

The purpose of this study is to evaluate efficacy and safety of mFOLFOX6+bevacizumab and mFOLFOX6+cetuximab for liver only metastasis from KRAS Exon 2 wild type (under protocol 1.0-1.2 edition) and RAS wild type (under protocol 2.0 edition) colorectal cancer.

Description: The purpose of this study is to evaluate efficacy and safety of mFOLFOX6+bevacizumab and mFOLFOX6+cetuximab for liver only metastasis from KRAS Exon 2 wild type (under protocol 1.0-1.2 edition) and RAS wild type (under protocol 2.0 edition) colorectal cancer.

Achievement of Improved Survival by Molecular Targeted Chemotherapy and Liver Resection for Not Optimally Resectable Colorectal Liver Metastases

Randomized Phase II Study of mFOLFOX6 + Bevacizumab or mFOLFOX6 + Cetuximab in Liver Only Metastasis From KRAS Wild Type Colorectal Cancer

pathologically confirmed R0 liver resection rate

All the assessment is repeated for a maximum of 4 years.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Novel PET/CT Imaging Biomarkers of CB-839 in Combination With Panitumumab and Irinotecan in Patients With Metastatic and Refractory RAS Wildtype Colorectal Cancer	NCT03263429	Colorectal Canc... Metastatic Colo... RAS Wild Type C... Refractory Colo...	Glutaminase Inh... Panitumumab Irinotecan Hydr... Laboratory Biom... Pharmacological... Imaging with 11...	18 Years -	Vanderbilt-Ingram Cancer Center
HMBD-001 in Advanced HER3 Positive Solid Tumours	NCT05057013	Bladder Cancer Triple Negative... Castration-resi... Cervical Cancer RAS Wild Type C... Endometrial Can... Gastric Cancer Hepatocellular ... Melanoma Non-small Cell ... Oesophageal Can... Ovarian Cancer Pancreatic Canc... Squamous Cell C...	HMBD-001	16 Years -	Cancer Research UK
Achievement of Improved Survival by Molecular Targeted Chemotherapy and Liver Resection for Not Optimally Resectable Colorectal Liver Metastases	NCT01836653	Liver Only Meta...	Bevacizumab Cetuximab L-OHP l-LV 5-FU 5-FU	20 Years - 80 Years	EPS Corporation
Novel PET/CT Imaging Biomarkers of CB-839 in Combination With Panitumumab and Irinotecan in Patients With Metastatic and Refractory RAS Wildtype Colorectal Cancer	NCT03263429	Colorectal Canc... Metastatic Colo... RAS Wild Type C... Refractory Colo...	Glutaminase Inh... Panitumumab Irinotecan Hydr... Laboratory Biom... Pharmacological... Imaging with 11...	18 Years -	Vanderbilt-Ingram Cancer Center

Spots Global Cancer Trial Database for ras wild type colorectal cancer