Medical Food for the Dietary Management of Metastatic Colorectal Cancer

• ClinicalTrials.gov Identifier: NCT05183295
• Recruitment Status: Not yet recruiting
• First Posted: January 10, 2022
• Last Update Posted: January 10, 2022
• Sponsor: Faeth Therapeutics
• Information provided by (Responsible Party): Faeth Therapeutics

Study Description

Brief Summary:

This is a single arm study evaluating the tolerability and markers of colorectal cancer with a specially designed medical food restricted in specific amino acids for the dietary management of subjects with metastatic colorectal cancer. Subjects will be receiving two FDA approved second line drug therapies, fluoropyrimidine and oxaliplatin ± bevacizumab (FOLFIRI + BEV) that are routinely prescribed in combination for metastatic colorectal cancer as part of their routine care.

Condition or disease	Intervention/treatment	Phase
Metastatic Colorectal Cancer	Other: NEAAR Medical Food	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Prospective Single Arm Medical Food Study to Evaluate a Standardized Nonessential Amino Acid Restriction (NEAAR) Medical Food for the Dietary Management of Metastatic Colorectal Cancer
• Estimated Study Start Date: January 3, 2022
• Estimated Primary Completion Date: December 31, 2023
• Estimated Study Completion Date: December 31, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Experimental: Nonessential Amino Acid Restriction (NEAAR) Medical Food; This is a single arm study in which all subjects will receive NEAAR medical food and standard of care FDA approved chemotherapy. Each week NEAAR medical food will be consumed 5 consecutive days followed by 2 days of habitual food.	Other: NEAAR Medical Food; All subjects will receive NEAAR Medical Food, a standardized non-essential amino acid restricted medical food, and will also receive standard of care FDA approved chemotherapy consisting of fluoropyrimidine and oxaliplatin ± bevacizumab (FOLFIRI + BEV).

Outcome Measures

Primary Outcome Measures :

1. Demonstrate tolerability of the NEAAR medical food. [ Time Frame: Through study completion, average of 6 months ]
   The primary endpoint is the rate of the most common Grade 3 and 4 adverse event (AE) related to the NEAAR medical food (when added to standard of care chemotherapy) regimen. This will be compared with the rate of the most common Grade 3 and 4 AE of the historical control (i.e. standard of care).

Secondary Outcome Measures :

1. Comparison of gene mutation and gene expression as predictors of management of disease with the NEAAR medical food, assessed in relation to: [ Time Frame: Through study completion, average of 6 months ]
   Absolute and relative change of biomarkers of interest, CA19-9 and CEA.
2. Comparison of gene mutation and gene expression as predictors of management of disease with the NEAAR medical food, assessed in relation to: [ Time Frame: Through study completion, average of 6 months ]
   Overall Response Rates using RECIST 1.1
3. Comparison of gene mutation and gene expression as predictors of management of disease with the NEAAR medical food, assessed in relation to: [ Time Frame: Through study completion, average of 6 months ]
   Progression-free Survival using RECIST 1.1
4. Comparison of gene mutation and gene expression as predictors of management of disease with the NEAAR medical food, assessed in relation to: [ Time Frame: Through study completion, average of 6 months ]
   Overall survival
5. Establish the impact of NEAAR medical food on ECOG (Eastern Cooperative Oncology Group) performance status and weight compared to historical controls [ Time Frame: Through study completion, average of 6 months ]
   ECOG Performance Status will be measured utilizing the ECOG performance status scale
6. Establish all plasma amino acid concentrations (nmol/mL) for the time period the subject is consuming NEAAR medical food and compare with baseline measurements. [ Time Frame: Through study completion, average of 6 months ]
7. Correlation and regression analysis with blood amino acid concentrations (nmol/mL) for: [ Time Frame: Through study completion, average of 6 months ]
   L-glutamine, L-glutamic acid, L-alanine, glycine, L-arginine, L-proline, L-aspartic acid, L-serine, L-asparagine, L-tyrosine, L-cysteine/L-cystine, L-lysine, L-valine, L-histidine, L-leucine, L-isoleucine, L-tryptophan, L-phenylalanine, L-methionine, L-threonine.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Histologically confirmed metastatic and unresectable CRC.
2. Age ≥ 18 years.
3. ECOG Performance Status of ≤ 1.
4. Subject is not receiving any other cancer therapy. Subjects participating in surveys or observational studies are allowed.

5. Has failed treatment for fluoropyrimidine and oxaliplatin ± BEV.

   1. All subjects must have received a minimum of 6 weeks of a first line regimen that included oxaliplatin and a fluoropyrimidine ± BEV. Treatment failure is defined as radiologic progression during or < 6 months after the last dose of first-line therapy.
   2. Subjects who show tumor progression while on maintenance therapy with a fluoropyrimidine ± BEV after prior fluoropyrimidine-oxaliplatin ± BEV induction therapy are eligible. Rechallenge with oxaliplatin is permitted and will be considered part of the first-line regimen for metastatic disease, with both initial oxaliplatin treatment and subsequent rechallenge being considered as one regimen.
   3. Subjects who received oxaliplatin/fluoropyrimidine-based neoadjuvant or adjuvant therapy and have disease recurrence or progression > 6 months from their last dose of neoadjuvant or adjuvant treatment (or > 6 months from surgery if no adjuvant therapy was administered) will be required to receive and progress on fluoropyrimidine/oxaliplatin-based therapy ± BEV for metastatic disease.
   4. For subjects with rectal cancer, sequential neoadjuvant and adjuvant therapy will count as a single systemic regimen.
   5. Subjects who discontinued first-line therapy because of toxicity may be enrolled as long as progression occurred < 6 months after the last dose of first-line therapy.
6. FOLFIRI ± BEV therapy is prescribed for the subject per standard of care.

7. Females of child-bearing potential (defined as a sexually mature woman who has not undergone hysterectomy or bilateral oophorectomy or has not been naturally postmenopausal for at least 24 consecutive months [i.e., has had menses at any time during the preceding 24 consecutive months]) must:

   1. Commit to true abstinence from heterosexual contact or agree to use, and be able to comply with, effective contraception without interruption until their final study visit and return to habitual food; and
   2. have a negative serum pregnancy test (β -hCG) result at screening. This applies even if the subject practices true abstinence from heterosexual contact.
8. Male subjects must commit to practicing true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential starting at screening until discontinuation from study, even if he has undergone a successful vasectomy. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
9. Subjects with measurable disease as determined by RECIST 1.1.

10. Must have acceptable organ function.

    1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (1500/μL).
    2. Platelet count ≥ 100 x 109/L.
    3. Hemoglobin ≥ 9 g/dL
    4. Activated partial thromboplastin time/international normalized ratio (aPTT/ INR) ≤ 1.5 x upper limit of normal (ULN) unless the subject is on anticoagulants in which case therapeutically acceptable values (as determined by the investigator) meet eligibility requirements.
    5. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤2.5 × ULN. In the case of known (i.e., radiological or biopsy documented) liver metastasis, serum transaminase levels must be ≤ 5 x ULN.
    6. Total serum bilirubin ≤ 1.5 x ULN (except for subjects with known Gilbert's Syndrome for which ≤ 3 x ULN is permitted).
    7. Serum creatinine < 2.0 x ULN and creatinine clearance ≥ 50mL/min/1.73m2.
    8. Serum albumin ≥3.5 mg/dL.
11. Subjects must have available colorectal cancer (CRC) tissue samples from a primary or metastatic site that has been biopsied within 6 months of the initial diagnosis of metastatic colorectal cancer and provide consent for them to be obtained and analyzed by the study sponsor to assist in determining final eligibility. A minimum of five (ten preferred) formalin fixed paraffin embedded (FFPE) archival or fresh tumor tissue slides are required.
12. Subjects must be willing to stop taking any supplements, herbal medicines, or alternative remedies or other prescribed or over the counter supplements for at least 1 week prior to Cycle 1 Day 1 of FOLFIRI ± BEV and through the NEAAR medical food period.

Exclusion Criteria:

1. Concomitant MSI-H/dMMR (Microsatellite Instability High/Deficient Mismatch Repair)
2. Anti-cancer chemotherapy or biologic therapy administered within 3 weeks prior to the first dose of fluoropyrimidine and irinotecan-based regimens . The exception is a single dose of radiation up to 8 Gray (equal to 800 RAD) with palliative intent for pain control up to 14 days before NEAAR medical food and return to baseline or ≤ Grade 1 toxicity associated with the radiation therapy.
3. More than one prior chemotherapy regimen administered in the metastatic setting.
4. Major surgery within 6 weeks prior to randomization.
5. Current brain metastasis.
6. Women who are pregnant or breastfeeding.
7. Gastrointestinal (GI) disorder(s) that, in the opinion of the investigator, would significantly impede the absorption of an oral agent (e.g., intestinal occlusion, active Crohn's disease, ulcerative colitis, extensive gastric, and small intestine resection). Exception: ostomy with normal daily stool output (<2L output).
8. Unable or unwilling to ingest the NEAAR medical food.

9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, clinically significant non-healing or healing wounds, symptomatic congestive heart failure (CHF) Class II or higher according to the New York Heart Association (NYHA) Functional Classification, unstable angina pectoris, clinically significant cardiac arrhythmia, cardiac stent placement < 3 months prior to the NEAAR run in period, significant pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection or psychiatric illness/social situations that would limit compliance with study requirements.

   1. Known active infection with Human Immunodeficiency Virus (HIV) and/or active infection with hepatitis B or C (patients who have had a hepatitis B virus [HBV] immunization are eligible).
   2. Clinically significant ascites or pleural effusions.
10. Diagnosis of another malignancy within the past 2 years (excluding a history of carcinoma in situ of the cervix, superficial non-melanoma skin cancer, superficial bladder cancer that has been adequately treated, or stage 1 prostate cancer that does not require treatment or requires only treatment with luteinizing hormone releasing hormone agonists or antagonists if initiated at least 30 days prior to beginning the NEAAR medical food).Any active disease condition that would render the protocol treatment dangerous or impair the ability of the patient to receive NEAAR

11. The following are exclusion criteria for patients who received SOC BEV:

    1. History of cardiac disease: congestive heart failure (CHF) Class II or higher according to the New York Heart Association (NYHA); active coronary artery disease, myocardial infarction within 6 months prior to study entry; unevaluated new onset angina within 3 months or unstable angina (angina symptoms at rest) or cardiac arrhythmias requiring antiarrhythmic therapy (beta blockers or digoxin are permitted).
    2. Current uncontrolled hypertension (systolic blood pressure [BP] > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management) or prior history of hypertensive crisis or hypertensive encephalopathy.
    3. History of arterial thrombotic or embolic events (within 6 months prior to study entry).
    4. Significant vascular disease (e.g., aortic aneurysm, aortic dissection, symptomatic peripheral vascular disease).
    5. Evidence of bleeding diathesis or clinically significant coagulopathy.
    6. Major surgical procedure (including open biopsy, significant traumatic injury, etc.) within 28 days, or anticipation of the need for major surgical procedure during the study, and minor surgical procedure (excluding placement of a vascular access device) within 7 days prior to study enrollment.
    7. Proteinuria at Screening as demonstrated by urinalysis with proteinuria ≥2+ (patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).
    8. History of abdominal fistula, GI perforation, peptic ulcer, or intraabdominal abscess within 6 months.
    9. Ongoing serious, non-healing wound, ulcer, or bone fracture.
    10. Known hypersensitivity to any component of BEV.
    11. History of reversible posterior leukoencephalopathy syndrome (RPLS).
12. Comorbidity risk, that in the discretion of the investigator would make the subject a poor candidate for the NEAAR medical food.
13. A body mass index (BMI) <20 kg/m2 or >40 kg/m2, or serious or refractive cachexia or anorexia that, in the investigator's opinion, realistically prohibits subjects from having energy or appetite sufficient to reliably engage in a strict medical food regimen for an extended time.
14. Insulin-dependent or poorly controlled diabetes.
15. Subjects who must take medications that impact targeted amino acid levels
16. Inability or unwillingness to comply with study and/or follow-up procedures, or medical food modifications described in the protocol.
17. Untreated clinically significant hyperlipidemia per investigator.
18. Subjects with a condition (including gallbladder disease and/or fatty acid oxidation disorders or porphyria) where high-fat or fatty food is contraindicated.
19. Presence of any condition (e.g., persistent diarrhea) that renders the subject unable to satisfactorily chew, swallow, digest, absorb, or tolerate the majority of foods and liquids of the NEAAR medical food, especially high-fat foods such as oils, cream, and butter.
20. Taking or needs to take any protein or amino acid containing nutritional supplements (e.g., Ensure®).
21. Lack of physical integrity of the upper or lower gastrointestinal (GI) tract.
22. History of confirmed food allergy.
23. Unwillingness to consume small quantities of meat products and byproducts (for example fish sauce, bone marrow, chicken broth, etc.).
24. Currently enrolled in any other investigational trial or treatment with investigational therapy(ies).
25. Diagnosis of previous or current eating disorder and/or disordered eating behaviors.
26. Diagnosed with Crohn's disease, ulcerative colitis, or gluten-sensitive enteropathy (Celiac disease).
27. Has previous epidermal growth factor receptor inhibitor (EGFRi) therapy or a combined fluoropyrimidine and irinotecan plus oxaliplatin-based regimen (e.g, FOLFIRINOX) in the first line treatment.
28. Is receiving or plans to receive a concomitant EGFRi inhibitor.
29. Individuals where severe constipation or exacerbation of constipation would not be advisable (e.g. small bowel obstruction)
30. Inability of a subject to, in the opinion of the investigator, maintain adequate nutrition or hydration status

Contacts and Locations

Contacts

Contact: Katelyn Patterson; 415-234-0538; katelyn@faeththerapeutics.com

Contact: Todd Young, MD; 650-515-7886; todd@faeththerapeutics.com

Locations

United States, California

Cedars-Sinai Health System

Beverly Hills, California, United States, 90210

Contact: Natalie Moshayedi 949-945-3501 Natalie.Moshayedi@cshs.org

Principal Investigator: Jun Gong, MD

Sponsors and Collaborators

Faeth Therapeutics

Investigators

• Principal Investigator: Andrea Cerceck, MD; Memorial Sloan Kettering Cancer Center

More Information

• Responsible Party: Faeth Therapeutics
• ClinicalTrials.gov Identifier: NCT05183295
• Other Study ID Numbers: NEAAR-002
• First Posted: January 10, 2022
• Last Update Posted: January 10, 2022
• Last Verified: December 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases