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

Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03263429
• Other study ID #: VICC GI 1703
• Secondary ID: NCI-2017-01461
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: August 23, 2017
• Est. completion date: December 1, 2024

Study information

• Verified date: March 2023
• Source: Vanderbilt-Ingram Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 29
• Est. completion date: December 1, 2024
• Est. primary completion date: December 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Signed and dated written informed consent

• Histologically or cytologically-confirmed diagnosis of metastatic KRAS wildtype colorectal cancer (CRC)

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• In dose escalation, patients must have had at least one prior line of chemotherapy for advanced disease or progressed within 6 months of adjuvant therapy (prior chemotherapy and/or anti-EGFR therapy is permitted)

• In dose expansion, patients must have received prior anti-EGFR therapy and achieved at least stable disease on at least one scan as their best response

• In dose expansion, patients must be willing to undergo a pre-treatment biopsy, and four research PET imaging techniques (11C-Glutamine and 18F-FSPG), two pre-treatment and two after one cycle of treatment

• In dose expansion, at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 which can be followed by CT or magnetic resonance imaging (MRI)

• Absolute neutrophil count (ANC) >= 1,500/uL

• Platelets >= 100,000/uL

• Serum albumin >= 3.0 g/dL

• Serum creatinine =< 2 mg/dL, or calculated creatinine clearance > 50 mL/min (per the Cockcroft-Gault formula)

• Total bilirubin =< 1.5 times upper limit of normal (ULN)

• Aspartate transaminase (AST) and alanine aminotransferase (ALT) =< 5.0 x ULN

• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 14 days prior to receiving first dose of protocol-indicated treatment; and additionally agree to use at least 2 methods of acceptable contraception or abstain from heterosexual intercourse from the time of signing consent, and until 2 months after patient's last dose of protocol-indicated treatment; WOCBP of childbearing potential are defined as those not surgically sterile or not post-menopausal (i.e. if a female patient has not had a bilateral tubal ligation, a bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 12 months in the absence of an alternative medical cause, then patient will be considered a female of childbearing potential); postmenopausal status in females under 55 years of age should be confirmed with a serum follicle-stimulating hormone (FSH) level within laboratory reference range for postmenopausal women

• Men able to father children who are sexually active with WOCBP must agree to use at least 2 methods of acceptable contraception from the time of signing consent and until 2 months after patient's last dose of protocol-indicated treatment; men able to father children are defined as those who are not surgically sterile (i.e. patient has not had a vasectomy)

Exclusion Criteria:

• Within 28 days before first dose of protocol-indicated treatment:

• Anti-cancer treatment including chemotherapy, radiation, hormonal therapy, targeted therapy, immunotherapy, or biological therapy

• Major surgery requiring general anesthesia; (Note: within this time frame, placement of a central line or portacath is acceptable and does not exclude)

• Receipt of an investigational agent

• Within 14 days before first dose of protocol-indicated treatment:

• Active uncontrolled infection; patients with infection under active treatment and controlled with antibiotics initiated at least 14 days prior to initiation of protocol-indicated treatment are not excluded (e.g. urinary tract infection controlled with antibiotics)

• Dose escalation only: known grade 4 toxicity probably or definitely attributed to past irinotecan treatment

• Active inflammatory bowel disease, other bowel disease causing chronic diarrhea (defined as > 4 loose stools per day), or bowel obstruction

• History of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline chest CT scan

• Unable to receive oral medication

• Central nervous system (CNS) metastasis, unless asymptomatic or previously treated and stable; and no evidence of CNS progression for at least 30 days prior to initiating protocol-indicated treatment; anticonvulsant and/or corticosteroid therapy will be allowed if patient is on a stable or decreasing dose of such treatment for at least 30 days prior to initiating protocol-indicated treatment

• Patients with known Gilbert's disease

• Patient is pregnant or breastfeeding

• Current or previous malignant disease (other than colorectal cancer) within the last 5 years; with the exception of the following if considered curatively treated: non-melanoma skin cancer(s), carcinoma in situ of the cervix, and ductal carcinoma in situ; subjects with another active malignancy requiring concurrent anti-cancer intervention are excluded; (Note the following does not exclude: effectively treated malignancy that has been in remission for more than 5 years and is considered to be cured AND no additional anti-cancer therapy is ongoing and required during the study period)

• Known positive test for human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), hepatitis A, hepatitis B, hepatitis C, or cytomegalovirus (CMV)

• Known psychiatric condition, social circumstance, or other medical condition reasonably judged by the patient's study physician to unacceptably increase the risk of study participation; or to prohibit the understanding or rendering of informed consent or anticipated compliance with scheduled visits, treatment schedule, laboratory tests and other study requirements.

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms
• Metastatic Colorectal Cancer
• RAS Wild Type Colorectal Cancer
• Refractory Colorectal Cancer

Intervention

Drug:
• Glutaminase Inhibitor CB-839
Given by mouth

Biological:
• Panitumumab
Given by vein

Drug:
• Irinotecan Hydrochloride (phase I only)
Given by vein

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Pharmacological Study
Correlative studies

Device:
• Imaging with 11C-Glutamine PET/CT scans and 18F-FSPG PET/CT scans
During phase II at baseline and day 28 of cycle 1

Locations

Country	Name	City	State
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee

Sponsors (3)

Lead Sponsor	Collaborator
Vanderbilt-Ingram Cancer Center	Calithera Biosciences, Inc, National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose (Phase I) B-839 in combination with panitumumab and irinotecan hydrochloride	The maximum tolerated dose will be determined	Up to 12 months
Primary	Response rate (Phase II)	Will use Simon's optimal 2-stage design to monitor efficacy in this trial.	Up to 12 months
Primary	Recommended phase 2 dose of CB-839 in combination with panitumumab and irinotecan hydrochloride (Phase I)	The recommended phase 2 dose will be determined.	Up to 12 months.
Secondary	Disease control rate	The disease control rate will be evaluated.	Up to 12 months
Secondary	Maximum Standardized Uptake Value (SUVmax) of fluorine F 18 L-glutamate derivative BAY94-9392 (18F-FSPG) uptake (Phase II)	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.	Up to 8 weeks
Secondary	Plasma exosomal content (phase II)	Plasma exosomal content will be assessed at pre-treatment, after one cycle of treatment, and at disease progression.	Up to 12 months
Secondary	Progression free survival (phase II)	will use Cox proportional hazards model to estimate the association between PET SUVmax and OS.	Up to 12 months
Secondary	Overall Survival	will use Cox proportional hazards model to estimate the association between PET SUVmax and OS.	Up to 12 months