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

• Glutaminase Inhibitor CB-839 (Drug): Given by mouth
• Panitumumab (Biological): Given by vein
• Irinotecan Hydrochloride (phase I only) (Drug): Given by vein
• Laboratory Biomarker Analysis (Other): Correlative studies
• Pharmacological Study (Other): Correlative studies
• Imaging with 11C-Glutamine PET/CT scans and 18F-FSPG PET/CT scans (Device): During phase II at baseline and day 28 of cycle 1

Primary outcomes

• Maximum Tolerated Dose (Phase I) of CB-839 in Combination With Panitumumab and Irinotecan Hydrochloride [Up to 12 months]: The maximum tolerated dose of CB-839 will be determined in Phase I with dose-escalation following Bayesian continual reassessment method. Patients were treated in cohort of 3. The CB839 dose leves were 400, 600 and 800mg.
• Response Rate (Phase II) [Up to 12 months]: The percent of patients with best response as complete response (CR) and partial response(PR) among patients with evaluable result. The response criteria: CR, Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, Progressive Disease (PD), At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition, the sum must also demonstrate an absolute increase of at least 5 mm. (The appearance of one or more new lesions is also considered progression); Stable Disease(SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
• Recommended Phase 2 Dose of CB-839 in Combination With Panitumumab and Irinotecan Hydrochloride (Phase I) [Up to 12 months.]: The recommended phase 2 dose will be determined.

Secondary outcomes

• Disease Control Rate [Up to 12 months]: The disease control rate will be evaluated. It is defined as the percent of patients with response as CR, PR, or SD among patients with evaluable result. The response criteria: CR, Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, Progressive Disease (PD), At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition, the sum must also demonstrate an absolute increase of at least 5 mm. (The appearance of one or more new lesions is also considered progression); Stable Disease(SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
• Coefficient of Determination (R2) of Maximum Standardized Uptake Value (SUVmax) of Fluorine F 18 L-glutamate Derivative BAY94-9392 (18F-FSPG) Uptake Change With Tumor Size Change (Phase II) [Up to 8 weeks]: Evaluate the relationship between 18F-FSPG uptake change from baseline and change in tumor size at the time of objective response assessment using a standard linear regression analysis. The coefficient of determination (R2) describes the strength of the relationship between the change in 18F-FSPG and the change in tumor size. The squared root of R2 is the correation coefficient between the change in 18F-FSPG and the change in tumor size. R2 is reported.
• Plasma Exosomal Content (Phase II) [Up to 12 months]: Plasma exosomal content will be assessed at pre-treatment, after one cycle of treatment, and at disease progression.
• Progression Free Survival (Phase II) [Up to 12 months]: It is defined as the time from on treatment to disease progression or death (whichever comes first). For those alive without progression, they were censored at last follow up date. Kaplan-Meier method was used to estimate the median survival time with 95% confidence interval.
• Overall Survival [Up to 12 months]: It is defined as the days from on treatment date to death due to any cause. Those alive were censored at the last date of follow up. Kaplan-Meier method was used to estimate the median survival time with 95% confidence interval.

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• Maximum Tolerated Dose (Phase I) of CB-839 in Combination With Panitumumab and Irinotecan Hydrochloride (Primary), Number, mg: Panitumumab/Irinotecan/CB-839 800
• Response Rate (Phase II) (Primary), Number, percentage of participants: CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) 11.8 (3.3 to 34.3)
• Recommended Phase 2 Dose of CB-839 in Combination With Panitumumab and Irinotecan Hydrochloride (Phase I) (Primary), Number, mg: Panitumumab/Irinotecan/CB-839 800
• Disease Control Rate (Secondary), Number, percentage of participants: CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) 41.2 (21.6 to 64.0)
• Coefficient of Determination (R2) of Maximum Standardized Uptake Value (SUVmax) of Fluorine F 18 L-glutamate Derivative BAY94-9392 (18F-FSPG) Uptake Change With Tumor Size Change (Phase II) (Secondary), Number, Coefficient of determination: CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) 0.0983
• Plasma Exosomal Content (Phase II) (Secondary), Mean, mg: CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) Pre-treatment 3.9 (3.5 to 4.4); CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) After Cycle 1 3.2 (2.7 to 3.7); CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) at Progression 4.1 (3.6 to 4.5)
• Progression Free Survival (Phase II) (Secondary), Median, days: CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) 56 (43 to 93)
• Overall Survival (Secondary), Median, days: CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) 265 (113 to 399)

Adverse events

Time frame: Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.

Serious adverse events by term

Other adverse events by term

102 more terms not shown.

• Study Protocol and Statistical Analysis Plan (PDF, 2022-01-06)
• Informed Consent Form (PDF, 2022-01-18)

• Jordan Berlin, MD, Principal investigator, Vanderbilt-Ingram Cancer Center