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Combination of Serabelisib and Insulin Suppressing Diet in Subjects With Advanced Solid Tumors With PIK3CA Mutations

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05300048
Recruitment Status : Recruiting
First Posted : March 29, 2022
Last Update Posted : May 26, 2022
Sponsor:
Information provided by (Responsible Party):
Faeth Therapeutics

Brief Summary:
This study will evaluate the feasibility of optimizing the safety and tolerability of serabelisib when combined with an ISD with a goal of reducing side effects and enhancing anticancer activity.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumor PIK3CA Mutation PTEN Loss of Function Mutation Drug: Serabelisib Other: Insulin Suppressing Diet Phase 1

Detailed Description:

Targeted anticancer drugs have side effects that often result in a poor quality of life, noncompliance, dose decreases, or discontinuation, all of which can affect efficacy. This study will evaluate the feasibility of optimizing the safety and tolerability of serabelisib when combined with an insulin suppressing diet with a goal of reducing side effects and enhancing anticancer activity.

Serabelisib is a small molecule with potent and selective inhibitory activity against the PI3K alpha isoform and has shown promising anticancer activity in preclinical models as a single agent. Preclinical studies have also shown that combining a phosphoinositide 3-kinase inhibition with an ISD resulted in improved efficacy in mouse tumor models as compared with PI3K inhibition alone.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 58 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Study of Serabelisib in Combination With an Insulin Suppressing Diet (Study ISD) in Subjects With Advanced Solid Tumors With PIK3CA Mutations With or Without PTEN Loss
Actual Study Start Date : April 22, 2022
Estimated Primary Completion Date : November 2023
Estimated Study Completion Date : November 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Insulin

Arm Intervention/treatment
Experimental: Cohort 1 - Dose Modification
10 Subjects with PIK3CA-mutated with or without PTEN loss solid tumors Dosing: Serabelisib PO on 3 consecutive days per week (3CDW) 600 mg starting dose. Adjusted to 900 mg , remain at 600 mg , or deescalate to 300 mg based on safety.
Drug: Serabelisib
The Study Drug, serabelisib is a class I phosphoinositide 3-kinase alpha PI3Kα) inhibitor. Serabelisib will be supplied as immediate-release tablets for oral (PO) administration.

Other: Insulin Suppressing Diet
The Study Drug must be consumed continuously on the 3CDW schedule without a break. The Study ISD will be delivered weekly and supplied as 3 pre-prepared meals (i.e., breakfast, lunch, dinner) and optional snacks provided dependent upon caloric needs. The meals must be consumed orally at the subject's usual times for breakfast, lunch, and dinner.

Experimental: Cohort 2 - Expansion Colorectal Cancer
16 Subjects with PIK3CA-mutated with or without PTEN loss colorectal cancer Dosing: RP2D (Recommended Phase 2 Dose)
Drug: Serabelisib
The Study Drug, serabelisib is a class I phosphoinositide 3-kinase alpha PI3Kα) inhibitor. Serabelisib will be supplied as immediate-release tablets for oral (PO) administration.

Other: Insulin Suppressing Diet
The Study Drug must be consumed continuously on the 3CDW schedule without a break. The Study ISD will be delivered weekly and supplied as 3 pre-prepared meals (i.e., breakfast, lunch, dinner) and optional snacks provided dependent upon caloric needs. The meals must be consumed orally at the subject's usual times for breakfast, lunch, and dinner.

Experimental: Cohort 3 - Expansion Endometrial Cancer
16 Subjects with PIK3CA-mutated with or without PTEN loss endometrial cancer Dosing: RP2D (Recommended Phase 2 Dose)
Drug: Serabelisib
The Study Drug, serabelisib is a class I phosphoinositide 3-kinase alpha PI3Kα) inhibitor. Serabelisib will be supplied as immediate-release tablets for oral (PO) administration.

Other: Insulin Suppressing Diet
The Study Drug must be consumed continuously on the 3CDW schedule without a break. The Study ISD will be delivered weekly and supplied as 3 pre-prepared meals (i.e., breakfast, lunch, dinner) and optional snacks provided dependent upon caloric needs. The meals must be consumed orally at the subject's usual times for breakfast, lunch, and dinner.

Experimental: Cohort 4 - Expansion Ovarian Clear Cell or Ovarian Endometrioid Carcinoma
16 Subjects with PIK3CA-mutated with or without PTEN loss ovarian clear cell or ovarian endometrioid carcinoma Dosing: RP2D (Recommended Phase 2 Dose)
Drug: Serabelisib
The Study Drug, serabelisib is a class I phosphoinositide 3-kinase alpha PI3Kα) inhibitor. Serabelisib will be supplied as immediate-release tablets for oral (PO) administration.

Other: Insulin Suppressing Diet
The Study Drug must be consumed continuously on the 3CDW schedule without a break. The Study ISD will be delivered weekly and supplied as 3 pre-prepared meals (i.e., breakfast, lunch, dinner) and optional snacks provided dependent upon caloric needs. The meals must be consumed orally at the subject's usual times for breakfast, lunch, and dinner.




Primary Outcome Measures :
  1. Cohort 1: Evaluate the safety of instrasubject modulated dosing for serabelisib in combination with a Study ISD in a pilot cohort. [ Time Frame: Through study completion, an average of 8 months. ]
    Incidence of related AEs due to serabelisib and/or Study ISD.

  2. Cohort 1: Evaluate the compliance of instrasubject modulated dosing for serabelisib in combination with a Study ISD in a pilot cohort. [ Time Frame: Through study completion, an average of 8 months. ]
    Compliance of Study ISD in combination with serabelisib as reported by the subject in the App for the ISD and as captured by teh site in the EDC from drug accountability.

  3. Cohort 1: Evaluate the pharmacokinetic impact of instrasubject modulated dosing for serabelisib in combination with a Study ISD in a pilot cohort by measuring Cmax. [ Time Frame: Through study completion, an average of 8 months. ]
    Standard pharmacokinetic parameters (Cmax)

  4. Cohort 1: Evaluate the pharmacokinetic impact of instrasubject modulated dosing for serabelisib in combination with a Study ISD in a pilot cohort by measuring Tmax. [ Time Frame: Through study completion, an average of 8 months. ]
    Standard pharmacokinetic parameters (Tmax).

  5. Cohort 1: Evaluate the pharmacokinetic impact of instrasubject modulated dosing for serabelisib in combination with a Study ISD in a pilot cohort by measuring AUC. [ Time Frame: Through study completion, an average of 8 months. ]
    Standard pharmacokinetic parameters (AUC).

  6. Cohorts 2, 3, 4: Use the Objective Response Rate (ORR) to assess the antitumor efficacy of serabelisib in combination with a Study ISD. [ Time Frame: Through study completion, an average of 8 months. ]
    Objective Response Rate (ORR), defined as the proportion of subjects who have best overall response of either complete response (CR) or partial response (PR)


Secondary Outcome Measures :
  1. Cohort 1: Antitumor efficacy of serabelisib in combination with a Study ISD by measuring ORR. [ Time Frame: Through study completion, an average of 8 months. ]
    ORR, defined as the proportion of subjects who have best overall response of either CR or PR, as determined by each site.

  2. Cohort 1: Antitumor efficacy of serabelisib in combination with a Study ISD by measuring PFS. [ Time Frame: Through study completion, an average of 8 months. ]
    PFS, defined as the time from date of first dose of Study Drug (Visit 1) to the date of first evidence of disease progression or death from any cause (whichever occurs first).

  3. Cohort 1: Antitumor efficacy of serabelisib in combination with a Study ISD by measuring OS. [ Time Frame: Through study completion, an average of 8 months. ]
    Overall survival (OS) and landmark survival.

  4. Cohort 1: Antitumor efficacy of serabelisib in combination with a Study ISD by measuring DoR. [ Time Frame: Through study completion, an average of 8 months. ]
    Duration of response (DoR) Disease control rate (DCR; CR + PR + stable disease [SD])

  5. Cohort 1: Antitumor efficacy of serabelisib in combination with a Study ISD by measuring DCR. [ Time Frame: Through study completion, an average of 8 months. ]
    Disease control rate (DCR; CR + PR + stable disease [SD])

  6. Cohort 2, 3, 4: Confirm the safety of serabelisib in combination with a Study ISD. [ Time Frame: Through study completion, an average of 8 months. ]
    Incidence of related AEs due to serabelisib and/or Study ISD.

  7. Cohort 2, 3, 4: Confirm the compliance of serabelisib in combination with a Study ISD. [ Time Frame: Through study completion, an average of 8 months. ]
    Compliance of Study ISD in combination with serabelisib as reported by the subject in the App for the ISD and as captured by the site in the EDC from drug accountability.

  8. Cohort 2, 3, 4: Additional assessments of antitumor efficacy of serabelisib in combination with a Study ISD (Measuring PFS). [ Time Frame: Through study completion, an average of 8 months. ]

    PFS

    DoR DCR (CR+PR+SD)


  9. Cohort 2, 3, 4: Additional assessments of antitumor efficacy of serabelisib in combination with a Study ISD (Measuring OS). [ Time Frame: Through study completion, an average of 8 months. ]
    OS and landmark survival

  10. Cohort 2, 3, 4: Additional assessments of antitumor efficacy of serabelisib in combination with a Study ISD (Measuring DoR). [ Time Frame: Through study completion, an average of 8 months. ]
    DoR

  11. Cohort 2, 3, 4: Additional assessments of antitumor efficacy of serabelisib in combination with a Study ISD (Measuring DCR). [ Time Frame: Through study completion, an average of 8 months. ]
    DCR (CR+PR+SD)



Information from the National Library of Medicine

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

Inclusion Criteria:

  1. Able to provide written informed consent.
  2. Age ≥18 at Visit -1 (screening).
  3. Histologically or cytologically confirmed recurrent solid tumors.

    1. Cohort 1: any extracranial solid tumor
    2. Cohort 2: adenocarcinoma of the colon or rectum.
    3. Cohort 3: recurrent or persistent endometrial adenocarcinoma with the following histologic epithelial cell types: endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified (N.O.S.), mucinous adenocarcinoma, squamous cell carcinoma, transitional cell carcinoma, and carcinosarcoma.
    4. Cohort 4: ovarian cancer primary tumor with ≥ 50% clear cell histomorphology or ovarian clear cell or ovarian endometrioid carcinoma
  4. Tumor must harbor an activating mutation in the PIK3CA gene with or without PTEN loss, either previously documented or determined during screening.
  5. Fresh or archival tumor biopsy with sufficient material to be sent to the designated laboratory for PD analyses. If only slides are available, then a minimum of 15 slides is required and the tumor tissue must have been obtained within 12 months of screening.
  6. Cohort 1 - Dose Modification (subjects with any solid tumor): failed, were intolerant of, or ineligible for no more than 3 prior lines of systemic therapy (LOTs) for advanced/metastatic disease (American Joint Committee on Cancer [AJCC] stage III and IV) or refused standard of care therapy.
  7. Cohorts 2, 3, and 4 - Cohort Expansion: failed, were intolerant of, ineligible for, or have refused standard of care therapy for advanced/metastatic disease (AJCC stage III and

    IV) and:

    1. Cohort 2 (subjects with colorectal cancer): Have failed no more than 2 prior LOT.
    2. Cohort 3 (subjects with endometrial cancer): Have no more than 2 prior LOT. Concurrent hormonal therapy is NOT allowed.
    3. Cohort 4 (subjects with ovarian clear cell or ovarian endometrioid carcinoma): Have no more than 1 prior LOT in a platinum resistant/platinum refractory setting. BRCA mutant subjects are excluded unless they have failed a previous LOT with a PARP inhibitor. (Note: a LOT is defined as having been administered in the metastatic/inoperable setting. Neoadjuvant or adjuvant therapies will not be counted as a LOT if administered ≥6 months ago.)
  8. Life expectancy of at least 3 months.
  9. Documented radiographic progression since the last treatment was administered with at least one measurable lesion (as defined by RECIST 1.1). One of the lesions has to be in a location that allows for the on-study biopsy.
  10. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1.
  11. Adequate organ function

    1. Absolute neutrophil count (ANC) ≥1.0 × 109/L, platelet count ≥75 × 109/L, and hemoglobin ≥8.5 gm/dL (may be transfused to reach this Hb level unless due to blood loss).
    2. Liver transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) ≤2.5 × upper limit of normal (ULN) (<5 × ULN if liver metastases are present), and total bilirubin ≤1.5 × ULN (<3 x ULN if subject has Gilbert Syndrome).
    3. INR ≤1.5 x ULN unless subject is on anticoagulants that would affect the INR, then INR must be in the desired therapeutic range as judged by the investigator.
    4. Albumin level ≥3.5 mg/dL or ≥ the lower limit of normal.
    5. Renal: Serum creatinine ≤2 x ULN (or if higher than the normal range, calculated creatinine clearance [CrCl] must be ≥51 mL/min/1.73 m2 by body surface area- modified Cockcroft-Gault or other appropriate formula; actual body weight must be used for calculation of CrCl unless BMI is >30 kg/m2, in which case, lean body weight must be used).
  12. Ability to take oral medication, be willing to adhere to study procedures and Study Drug administration, and receive, consume, and comply with Study ISD.
  13. For women of childbearing 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]), a negative serum pregnancy test collected at screening (V-1) and negative urine pregnancy test collected at baseline (V0) and use of physician-approved method of birth control from the time of the pregnancy test performed at Screening to 90 days following the last administration of Study Drug.
  14. Male subjects must be surgically sterile or must agree to use physician-approved contraception during the study and for 90 days following the last administration of Study Drug.

Exclusion Criteria:

  1. Diagnosis of primary brain tumor.
  2. Has had serabelisib, alpelisib, or other PIK3 kinase inhibitor.
  3. Leptomeningeal disease and symptomatic or untreated brain metastases. Subjects with treated (surgically excised or irradiated) and stable brain metastases are eligible, assuming adequate recovery from treatment to Grade 1 or less, the treatment was at least 28 days prior to first planned administration of Study Drug, and baseline brain computed tomography (CT) with contrast or magnetic resonance imaging (MRI) within 14 days of initiation of Study Drug, is negative for new or worsening brain metastases.
  4. Diagnosis of, or requiring treatment for, another malignancy within the past 2 years (excluding a history of carcinoma in situ of the cervix, superficial non-melanoma skin cancer, or 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 90 days prior to the first planned dose of Study Drug).
  5. Is less than 21 days from therapeutic radiation or chemotherapy prior to the first planned day of dosing with Study Drug and has not recovered to Grade ≤ 1 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5.0, Appendix 5) from all clinically significant toxicities related to prior therapies.
  6. For subjects receiving nitrosoureas or mitomycin C, the subject is < 6 weeks from last dose. For monoclonal antibody therapy, the subject is < one half-life or <4 weeks from the last dose.
  7. Chronic, systemically administered glucocorticoids in doses equivalent to >5 mg prednisone daily. Topical, inhalational, ophthalmic, intraarticular, and intranasal glucocorticoids are permitted. Isolated or intermittent use of systemically administered glucocorticoids to treat complications of malignancy, use as a premedication, or as a one-time prep for an imaging procedure is permitted. If subject was on >5 mg prednisone/day equivalent, last dose must have been at least 7 days prior to the first planned dose of Study Drug. Replacement corticosteroids for adrenal insufficiency are permitted.
  8. Diabetes mellitus requiring insulin or insulin secretagogue therapy.
  9. Poorly controlled diabetes mellitus defined as glycosylated hemoglobin A1c (HbA1c) >7.5% or fasting blood sugar >160 mg/ dL.
  10. Known impaired cardiac function or clinically significant cardiac disease such as ventricular arrhythmia requiring therapy, congestive heart failure (New York Heart Association Class III or IV), and/or uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg on antihypertensive medications).
  11. Myocardial infarction, cardiac stent placement, or unstable angina within 6 months before the planned first administration of Study Drug.
  12. Have clinically significant peripheral vascular disease.
  13. Manifestations of malabsorption due to prior GI surgery, GI disease, or for an unknown reason that could alter the absorption of oral medications or Study ISD.
  14. Other clinically significant comorbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection (any infection requiring systemic therapy), non-healing wounds or injuries, or any other condition that could compromise the subject's participation or confound the interpretation of compliance, adherence, safety, or efficacy results.
  15. Pregnant (positive serum pregnancy test), planning to become pregnant during the study, or breastfeeding/planning to breastfeed during the study.
  16. Have taken strong CYP3A4 inducers/inhibitors within 7 days before the first administration of serabelisib (See Section 12.2 for list of strong CYP3A4 inducers/inhibitors) or have conditions that require the concomitant use of CYP3A4 inducers/inhibitors.
  17. Untreated or poorly controlled, gastro-esophageal reflux disease.
  18. Have taken histamine-H2 receptor antagonists within 24 hours before the planned first administration of serabelisib.
  19. Have taken proton-pump inhibitors (PPI) within 7 days or 5 half-lives (whichever is the shorter duration) before the first planned administration of serabelisib or are anticipated to need PPI during the study.
  20. Have taken neutralizing antacids within 4 hours before the first planned administration of serabelisib or are anticipated to need frequent antacid use during the study.
  21. Known to be positive for Human Immunodeficiency Virus, Hepatitis B, or Hepatitis C.
  22. Known allergies to serabelisib excipients or the ISD

    1. Serabelisib excipients: microcrystalline cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate (non-bovine).
    2. ISD allergens: milk, eggs, fish, Crustacean shellfish, tree nuts, peanuts, wheat, and soybeans.
  23. Severe, uncontrolled gout.
  24. A BMI <20 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.
  25. Any condition that renders the subject unable to satisfactorily chew, swallow, digest, or tolerate (i.e., persistent diarrhea) the majority of foods and liquids of the Study ISD.
  26. History of severe nephrolithiasis requiring urologic intervention.
  27. Participation in a diet (Atkins, Weight Watchers, Best Life, Nutrisystem, South Beach, Jenny Craig, Paleo Diet, Zone, etc.) or weight loss plan within 10 days prior to the planned first administration of Study Drug.
  28. Severe constipation or condition where exacerbation of constipation is not advisable (eg, small bowel obstruction history).
  29. History of anaphylaxis from food allergy or other disease state requiring avoidance of a particular food, such as celiac disease.
  30. Diagnosed eating disorder in the past 10 years.
  31. Unwilling to take a non-vegan or non-vegetarian diet.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05300048


Contacts
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Contact: Study Inquiry (650) 488-1109 clinicaltrials@faeththerapeutics.com

Locations
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United States, Alabama
University of Alabama Recruiting
Birmingham, Alabama, United States, 35429
Contact: Jill Hyde    205-975-2362    jspratlin@uabmc.edu   
United States, California
Pacific Cancer Specialists Recruiting
Anaheim, California, United States, 92801
Contact: Elizabeth Brown    714-999-1465    elizabethg@pacificcancer.com   
Hoag Memorial Hospital Presbyterian Recruiting
Newport Beach, California, United States, 92663
Contact: Leila Andres    949-764-8092    Leila.Andres@hoag.org   
Contact: Ryan Helber    949-764-4430    Ryan.Helber1@hoag.org   
United States, Illinois
University of Chicago Not yet recruiting
Chicago, Illinois, United States, 60637
Contact: Clinical Research Staff    773-702-1000    cancerclinicaltrials@bsd.uchicago.edu   
United States, Minnesota
Mayo Clinic - Rochester Not yet recruiting
Rochester, Minnesota, United States, 55902
Contact: Recruitment Hotline    855-776-0015    MAYOCLINICCANCERSTUDIES@mayo.edu   
United States, New York
Memorial Sloan Kettering Cancer Center Not yet recruiting
New York, New York, United States, 10065
Contact: Vickie Makker    646-888-4224    makkerv@mskcc.org   
United States, North Carolina
East Carolina University Not yet recruiting
Greenville, North Carolina, United States, 27858
Contact: Hematology Oncology Clinical Trials Office    252-816-2273    hemoncclinicaltrials@ecu.edu   
United States, South Dakota
Avera Cancer Institute Recruiting
Sioux Falls, South Dakota, United States, 57105
Contact: David Starks    605-322-7535    david.starks@avera.org   
United States, Texas
University of Texas Southwestern Not yet recruiting
Dallas, Texas, United States, 75390
Contact: Martha Cruz    214-648-7097    martha.cruz@utsw.edu   
United States, Wisconsin
Medical College of Wisconsin Not yet recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Clinical Trials Office    414-805-6800    cccto@mcw.edu   
Sponsors and Collaborators
Faeth Therapeutics
Investigators
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Principal Investigator: Vicky Makker Memorial Sloan Kettering Cancer Center
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Responsible Party: Faeth Therapeutics
ClinicalTrials.gov Identifier: NCT05300048    
Other Study ID Numbers: SER-ISD1-001
First Posted: March 29, 2022    Key Record Dates
Last Update Posted: May 26, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Faeth Therapeutics:
PIK3CA Mutation
PTEN Loss of Function Mutation
Additional relevant MeSH terms:
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Neoplasms
Serabelisib
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action