Combination of Serabelisib and Insulin Suppressing Diet With or Without Nab-paclitaxel in Subjects With Advanced Solid Tumors With PIK3CA Mutations

• ClinicalTrials.gov Identifier: NCT05300048
• Recruitment Status: Recruiting
• First Posted: March 29, 2022
• Last Update Posted: May 1, 2023
• Sponsor: Faeth Therapeutics
• Information provided by (Responsible Party): Faeth Therapeutics

Study Description

Brief Summary:

This study will evaluate the feasibility of optimizing the safety and tolerability of serabelisib (an investigational PI3K inhibitor) when combined with an ISD and with or without nab-paclitaxel 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; Drug: Nab paclitaxel	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 and with or without nab-paclitaxel with a goal of reducing side effects and enhancing anticancer activity.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 68 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) and With or Without Nab-paclitaxel in Adult Subjects With Advanced Solid Tumors With PIK3CA Mutations With or Without PTEN Loss
• Actual Study Start Date: April 22, 2022
• Estimated Primary Completion Date: September 2024
• Estimated Study Completion Date: September 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1a - Dose Modification without nab-paclitaxel; Subjects with any solid tumor will receive multiple doses of serabelisib administered orally and will consume Insulin Suppressing Diet for up to 12 months	Drug: Serabelisib; serabelisib administered orally; Other: Insulin Suppressing Diet; 3 meals consumed daily (i.e., breakfast, lunch, dinner) and optional snacks provided dependent on caloric needs
Experimental: Cohort 1b - Dose Modification with Nab-Paclitaxel; Subjects with endometrial cancer, ovarian clear cell or ovarian endometriod carcinoma will receive multiple doses of serabelisib administered orally and will consume Insulin Suppressing Diet for up to 12 months. In addition, these subjects will receive nab-paclitaxel intravenously weekly.	Drug: Serabelisib; serabelisib administered orally; Other: Insulin Suppressing Diet; 3 meals consumed daily (i.e., breakfast, lunch, dinner) and optional snacks provided dependent on caloric needs; Drug: Nab paclitaxel; nab-paclitaxel administered intravenously weekly
Experimental: Cohort 2 - Expansion Colorectal Cancer; Subjects will receive dose of serabelisib as determined from Cohort 1a and 1b, and will consume Insulin Suppressing Diet for up to 12 months	Drug: Serabelisib; serabelisib administered orally; Other: Insulin Suppressing Diet; 3 meals consumed daily (i.e., breakfast, lunch, dinner) and optional snacks provided dependent on caloric needs
Experimental: Cohort 3 - Expansion Endometrial Cancer; Subjects will receive dose of serabelisib as determined from Cohort 1a and 1b, and will consume Insulin Suppressing Diet for up to 12 months. If results from Cohort 1b show a favorable risk-benefit ratio, nab-paclitaxel will be administered intravenously weekly.	Drug: Serabelisib; serabelisib administered orally; Other: Insulin Suppressing Diet; 3 meals consumed daily (i.e., breakfast, lunch, dinner) and optional snacks provided dependent on caloric needs; Drug: Nab paclitaxel; nab-paclitaxel administered intravenously weekly
Experimental: Cohort 4 - Expansion Ovarian Clear Cell or Ovarian Endometrioid Carcinoma; Subjects will receive dose of serabelisib as determined from Cohorts 1a and 1b, and will consume Insulin Suppressing Diet for up to 12 months. If results from Cohort 1b show a favorable risk-benefit ratio, nab-paclitaxel will be administered intravenously weekly.	Drug: Serabelisib; serabelisib administered orally; Other: Insulin Suppressing Diet; 3 meals consumed daily (i.e., breakfast, lunch, dinner) and optional snacks provided dependent on caloric needs; Drug: Nab paclitaxel; nab-paclitaxel administered intravenously weekly

Outcome Measures

Primary Outcome Measures :

1. Cohorts 1a/1b: Evaluate safety [ Time Frame: Through study completion, up to 12 months. ]
   Incidence of related AEs
2. Cohorts 1a/1b: Evaluate compliance [ Time Frame: Through study completion, up to 12 months. ]
   Compliance of Study intervention
3. Cohorts 1a/1b: Evaluate the pharmacokinetic impact by measuring Cmax. [ Time Frame: Through study completion, up to 12 months. ]
   Standard pharmacokinetic parameters (Cmax)
4. Cohorts 1a/1b: Evaluate the pharmacokinetic impact by measuring Tmax. [ Time Frame: Through study completion, up to 12 months. ]
   Standard pharmacokinetic parameters (Tmax).
5. Cohorts 1a/1b: Evaluate the pharmacokinetic impact by measuring AUC. [ Time Frame: Through study completion, up to 12 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. ]
   Proportion of subjects who have best overall response of either complete response (CR) or partial response (PR)

Secondary Outcome Measures :

1. Cohorts 1a/1b: Antitumor efficacy of study intervention by measuring ORR. [ Time Frame: Through study completion, up to 12 months. ]
   Proportion of subjects who have best overall response of either CR or PR, as determined by each site.
2. Cohorts 1a/1b: Antitumor efficacy of study intervention by measuring PFS. [ Time Frame: Through study completion, up to 12 months. ]
   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. Cohorts 1a/1b: Antitumor efficacy of study intervention by measuring OS. [ Time Frame: Through study completion, up to 12 months. ]
   Overall survival (OS) and landmark survival.
4. Cohorts 1a/1b: Antitumor efficacy of study intervention by measuring DoR. [ Time Frame: Through study completion, up to 12 months. ]
   Duration of response (DoR)
5. Cohorts 1a/1b: Antitumor efficacy of study intervention by measuring DCR. [ Time Frame: Through study completion, up to 12 months. ]
   Disease control rate (DCR; CR + PR + stable disease [SD])
6. Cohort 2, 3, 4: Confirm safety [ Time Frame: Through study completion, up to 12 months. ]
   Incidence of related AEs
7. Cohort 2, 3, 4: Confirm the compliance of study intervention. [ Time Frame: Through study completion, up to 12 months. ]
   Compliance of Study intervention
8. Cohort 2, 3, 4: Additional assessments of antitumor efficacy of study intervention (Measuring PFS). [ Time Frame: Through study completion, up to 12 months. ]
   Time from the 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)
9. Cohort 2, 3, 4: Additional assessments of antitumor efficacy of study intervention (Measuring OS). [ Time Frame: Through study completion, up to 12 months. ]
   OS and landmark survival
10. Cohort 2, 3, 4: Additional assessments of antitumor efficacy of study intervention (Measuring DoR). [ Time Frame: Through study completion, up to 12 months. ]
    DoR
11. Cohort 2, 3, 4: Additional assessments of antitumor efficacy of study intervention (Measuring DCR). [ Time Frame: Through study completion, up to 12 months. ]
    DCR (CR+PR+SD)
12. Cohort 2, 3, 4: Assess the population PK and intra-tumoral concentration of study intervention. [ Time Frame: Through study completion, up to 12 months. ]
    Standard PK Parameters (Cmax) in plasma.
13. Cohort 2, 3, 4: Assess the population PK and intra-tumoral concentration of study intervention. [ Time Frame: Through study completion, up to 12 months. ]
    Standard PK Parameters (Tmax) in plasma
14. Cohort 2, 3, 4: Assess the population PK and intra-tumoral concentration of study intervention. [ Time Frame: Through study completion, up to 12 months. ]
    Standard PK Parameters (AUC) in plasma
15. Cohort 2, 3, 4: Assess the population PK and intra-tumoral concentration of study intervention. [ Time Frame: Through study completion, up to 12 months. ]
    Serabelisib concentration in tumor tissue

Other Outcome Measures:

1. Cohorts 1a/1b, 2, 3, 4: Assessment of PD of study intervention. [ Time Frame: Through study completion, up to 12 months. ]
   Change in PD markers (insulin)
2. Cohorts 1a/1b, 2, 3, 4: Assessment of PD of study intervention. [ Time Frame: Through study completion, up to 12 months. ]
   Change in PD markers (glucose)
3. Cohorts 1a/1b, 2, 3, 4: Assessment of PD of study intervention. [ Time Frame: Through study completion, up to 12 months. ]
   Change in biomarkers of insulin-PI3K signaling
4. Cohorts 1a/1b, 2, 3, 4: Assessment of PD of study intervention. [ Time Frame: Through study completion, up to 12 months. ]
   Changes in tumor marker levels.
5. Cohorts 1a/1b, 2, 3, 4: Assessment of immune markers in response to study intervention. [ Time Frame: Through study completion, up to 12 months. ]
   Assessment of immune markers in PBMCs throughout study.
6. Cohorts 1a/1b, 2, 3, 4: Assessment of genetic predictors of efficacy. [ Time Frame: Through study completion, up to 12 months. ]
   Analysis into whether the genetic status of the patient predicts a positive or negative therapeutic response (efficacy).
7. Cohorts 1a/1b, 2, 3, 4: Assessment of genetic predictors of toxicity. [ Time Frame: Through study completion, up to 12 months. ]
   Analysis into whether the genetic status of the patient predicts susceptibility to AEs (toxicity).

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. Able to provide written informed consent.
2. Age ≥18 at Visit -1 (screening).

3. Histologically or cytologically confirmed recurrent solid tumors.

   1. Cohort 1a: any extracranial solid tumor (may include EC, ovarian clear cell, or ovarian endometrioid carcinoma if subject is not eligible for nab-paclitaxel in Cohort

      1b)

   2. Cohort 1b: either recurrent or persistent endometrial adenocarcinoma (EC) 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 or; ovarian cancer (OC) with the primary tumor having ≥ 50% clear cell histomorphology or ovarian clear cell or ovarian endometrioid carcinoma.
   3. Cohort 2: adenocarcinoma of the colon or rectum.
   4. Cohort 3: recurrent or persistent endometrial adenocarcinoma with the following histologic epithelial cell types as described for Cohort 1b
   5. Cohort 4: OC primary tumor carcinomas as described for Cohort 1b
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. For subjects who consent to future research, an additional 5 slides from a surgical specimen or biopsy is required.
6. Cohort 1a - Dose Modification (subjects with any solid tumor): failed, were intolerant of, or ineligible for no more than three prior lines of therapy (LOT) for advanced/metastatic disease or refused SOC therapy.
7. For all cohorts, in the unlikely scenario that a subject refused all available SOC they may proceed with trial. These subjects would be regarded as having 0 prior LOT.

8. Cohorts 1b, 2, 3, and 4 - failed, were intolerant of, ineligible for, or have refused SOC therapy for advanced/metastatic disease (AJCC stage III and IV) and:

   1. Cohort 2 (subjects with colorectal cancer): Have failed no more than two prior LOT for metastatic CRC.
   2. Cohort 1b, and Cohort 3 (subjects with EC): Have no more than three prior chemotherapeutic regimens for management of endometrial carcinoma (neo-adjuvant and/or adjuvant chemotherapy will be counted as one prior LOT). Prior hormonal therapy will not count as a systemic regimen.
   3. Cohort 1b, and Cohort 4 (subjects with clear cell or endometrioid OC): Subjects must have had no more than three prior chemotherapeutic regimens for management of ovarian carcinoma. Prior hormonal therapy will not count as a systemic regimen.
9. Life expectancy of at least 3 months.
10. At least one measurable lesion (as defined by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1).
11. ECOG PS of 0 to 1.

12. Adequate organ function

    1. Absolute neutrophil count (ANC) ≥1.0 × 10^9/L or ≥1.5 x 10^9/L if planned to be treated with nab-paclitaxel, platelet count ≥75 × 10^9/L, and hemoglobin ≥8.5 gm/dL (may be transfused to reach this hemoglobin level unless due to blood loss).
    2. Liver transaminases (AST and 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 ≥3.0 mg/dL or ≥ the lower limit of normal.
    5. Renal: Serum creatinine ≤2 x ULN
13. Ability to take PO medication, be willing to adhere to study procedures and Study Intervention administration, and receive, consume, and comply with Study ISD.
14. For women of child-bearing potential, a negative serum pregnancy test collected at screening (Visit-1) and negative urine pregnancy test collected at baseline (Visit-1) 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 or, if applicable, 6 months following the last administration of nab-paclitaxel.
15. 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 malignant brain tumor.
2. Has had serabelisib, alpelisib, or other PI3K inhibitor.
3. Leptomeningeal disease and symptomatic or untreated 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 dose of Study Drug).
5. Is less than 21 days from therapeutic radiation or chemotherapy prior to the first day of dosing with Study Drug and has not recovered to Grade ≤ 1 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 < 1 half-life or <4 weeks from the last dose.
7. Chronic, systemically administered glucocorticoids in doses equivalent to >5 mg prednisone daily. 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.
11. QTcF interval >470 msec found at screening.
12. Myocardial infarction, cardiac stent placement, or unstable angina within 6 months before the first administration of Study Drug.
13. Have clinically significant peripheral vascular disease.
14. Manifestations of malabsorption
15. Other clinically significant comorbidities.
16. Pregnant (positive serum pregnancy test), planning to become pregnant during the study, or breastfeeding/planning to breastfeed during the study.
17. Have taken strong CYP3A4 inducers/inhibitors within 7 days before the first administration of serabelisib or have conditions that require the concomitant use of CYP3A4 inducers/inhibitors.
18. Untreated or poorly controlled, gastro-esophageal reflux disease.
19. Have taken histamine-H2 receptor antagonists within 12 hours before the first administration of serabelisib.
20. Have taken PPI within 7 days or 5 half-lives (whichever is the shorter duration) before the first administration of serabelisib or are anticipated to need PPI during the study.
21. Have taken neutralizing antacids within 4 hours before the first administration of serabelisib or are anticipated to need frequent antacid use during the study.
22. Subjects with poorly controlled human immunodeficiency virus, hepatitis B virus, and/or hepatitis C virus infections.
23. Known allergies to nab-paclitaxel or excipients, serabelisib or excipients or the ISD
24. Severe, uncontrolled gout.
25. A BMI <18.5 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 ISD regimen for an extended time.
26. 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.
27. History of severe nephrolithiasis requiring urologic intervention.
28. Participation in a diet or weight loss plan within 10 days prior to the first administration of Study Drug.
29. Severe constipation or condition where exacerbation of constipation is not advisable (eg, small bowel obstruction history).
30. History of anaphylaxis from food allergy or other disease state requiring avoidance of a particular food, such as celiac disease.
31. Diagnosed eating disorder in the past 10 years.
32. Unwilling to take a non-vegan or non-vegetarian diet.
33. Peripheral neuropathy ≥ CTC Grade 2

Contacts and Locations

Contacts

Contact: Study Inquiry; (708) 406-9282‬; clinicaltrials@faeththerapeutics.com

Locations

United States, Alabama

University of Alabama; Recruiting

Birmingham, Alabama, United States, 35429

Contact: Susan Pruitt smpruitt@uabmc.edu

Contact: Nichlas Fuhrmann nfuhrmann@uabmc.edu

United States, California

Pacific Cancer Specialists; Recruiting

Anaheim, California, United States, 92801

Contact: Elizabeth Brown 714-999-1465 elizabethg@pacificcancer.com

Valkyrie Clinical Trials; Recruiting

Los Angeles, California, United States, 90067

Contact: Micah Brill 951-417-2766 micah.brill@valkyrieclinicaltrials.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, Indiana

Community Health Network, Inc.; Recruiting

Indianapolis, Indiana, United States, 46250

Contact: Cindy Stoner 317-621-3836 cstoner@ecommunity.com

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

Northwell Health; Not yet recruiting

Lake Success, New York, United States, 11042

Contact: Iris Elledge 516-304-4442 ielledge@northwell.edu

Memorial Sloan Kettering Cancer Center; Recruiting

New York, New York, United States, 10065

Contact: Maria Rubinstein 646-888-6954 rubinstm@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, Pennsylvania

University of Pennsylvania Health System, Perelman Center for Advanced Medicine; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Katie Elkins katie.elkins@pennmedicine.upenn.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

Baptist Hospitals of Southeast Texas; Recruiting

Beaumont, Texas, United States, 77701

Contact: Telice Terro 409-212-5979 Telice.Terro@bhset.net

University of Texas Southwestern; Not yet recruiting

Dallas, Texas, United States, 75390

Contact: Martha Cruz 214-648-7097 martha.cruz@utsw.edu

Oncology Consultants, PA; Recruiting

Houston, Texas, United States, 77030

Contact: Julio Peguero 713-600-0913 jpeguero@oncologyconsultants.com

Lumi Research; Recruiting

Kingwood, Texas, United States, 77339

Contact: Scott Ward 832-319-1553 scott@lumiresearch.com

United States, Wisconsin

Medical College of Wisconsin; Active, not recruiting

Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

Faeth Therapeutics

Investigators

• Principal Investigator: Vicky Makker; Memorial Sloan Kettering Cancer Center

More Information

• Responsible Party: Faeth Therapeutics
• ClinicalTrials.gov Identifier: NCT05300048
• Other Study ID Numbers: SER-ISD1-001
• First Posted: March 29, 2022
• Last Update Posted: May 1, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

Neoplasms; Paclitaxel; Serabelisib; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors