Phase 2 Basket Trial of Nab-sirolimus in Patients With Malignant Solid Tumors With Pathogenic Alterations in TSC1/TSC2 Genes (PRECISION 1)

Phase 2

Active, not recruiting

• Conditions: Neoplasms; TSC1; Malignant Solid Tumor; Malignant Solid Neoplasm; Cancer Metastatic; Solid Tumor; Malignant Neoplasm; Tumor; Tumor, Solid; Metastasis
• Interventions: Drug: nab-sirolimus

• Registration Number: NCT05103358
• Lead Sponsor: Aadi Bioscience, Inc.

Brief Summary

A Phase 2 multi-center open-label basket trial of nab-sirolimus for adult and adolescent patients with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 genes

Detailed Description

Study TSC-007 is a prospective phase 2, open-label, multi-institutional basket trial to determine the efficacy and safety profile of nab-sirolimus administered to patients with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 genes. Patients will be treated with single agent IV nab-sirolimus until disease progression, or unacceptable toxicity, or until in the opinion of the investigator the patient is no longer benefiting from therapy, or at patient discretion.

Study Timeline

• Study First Submitted: 2021-10-22
• Study First Submitted QC: 2021-10-22
• Study First Posted: 2021-11-02
• Study Start: 2022-02-15
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-31
• Last Update Posted: 2024-06-03
• Primary Completion: 2024-12-31
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 120

Inclusion Criteria

1. Patients must have a malignant solid tumor with a pathogenic inactivating TSC1 or TSC2 alteration. Genetic alterations should be identified using NGS in tumor tissue or liquid biopsy).

   • Patients will be enrolled after the central evaluation of NGS report confirms eligibility.

2. Patients must have solid tumors that are metastatic or locally advanced where surgical resection is not an option or likely to result in severe morbidity.

3. Patients must have received all standard therapies appropriate for their tumor type and stage of disease or, in the opinion of the Investigator, the patient would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy, or the patient has no satisfactory alternative treatments.

4. Patients must have 1 or more measurable target lesions by computed tomography (CT) scan or magnetic resonance imaging (MRI) (RECIST v1.1).

5. Age: 12 years or older.

6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 or Karnofsky Performance Status (KPS) ≥80 or Lansky play-performance scale for pediatric patients ≥80.

7. Adequate liver function:

   1. Total bilirubin ≤1.5 × upper limit of normal (ULN) (unless due to Gilbert's syndrome, then ≤3 × ULN)
   2. Aspartate aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN if attributable to liver metastases)

8. Adequate renal function: creatinine clearance ≥30 mL/min, Cockcroft-Gault CCr = ((140-age) × weight[kg]) / (72 × SCr[mL/min]) × 0.85, if female

9. Adequate hematologic parameters:

   1. Absolute neutrophil count (ANC) ≥1.0 × 109/L (growth factor support allowed)
   2. Platelet count ≥100,000/mm3 (100 × 109/L) (transfusion and/or growth factor support allowed)
   3. Hemoglobin ≥8.0 g/dL (transfusion and/or growth factor support allowed)

10. Fasting serum triglyceride must be ≤300 mg/dL; fasting serum cholesterol must be ≤350 mg/dL.

11. Minimum of 4 weeks since any major surgery, completion of radiation, or completion of prior systemic anticancer therapy, or at least 5 half-lives if the prior therapy is a single agent small-molecule therapeutic, and adequately recovered from the acute toxicities of any prior therapy, including neuropathy, to Grade ≤1.

12. Male or non-pregnant and non-breastfeeding female:

    1. Females of childbearing potential must agree to use effective contraception or abstinence without interruption from 28 days prior to starting investigational product (IP) throughout 3 months after last dose of IP and have a negative serum pregnancy test (beta human chorionic gonadotropin, β-hCG) result at screening and agree to ongoing pregnancy testing during the course of the study, and after the end of study treatment. A second form of birth control is required even if she has had a tubal ligation.
    2. Male patients must agree not to donate sperm and must practice abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study and throughout 3 months after last dose of IP. A second form of birth control is required even if he has undergone a successful vasectomy.

13. The patient or the patient's parent(s) or legal guardian(s) understand(s) and sign(s) the informed consent.

14. Willingness and ability to comply with scheduled visits, laboratory tests, and other study procedures.

Exclusion Criteria

1. Prior treatment with an mTOR inhibitor, including nab-sirolimus.

2. Severe (Grade ≥3) ongoing infection requiring parenteral or oral anti-infective treatment, either ongoing or completed ≤7 days prior to enrollment.

3. Patients with primary brain tumors or PEComa.

4. Patients who have any severe and/or uncontrolled medical or psychiatric conditions or other conditions that could affect their participation including:

   1. Patients with meningeal carcinomatosis, leptomeningeal carcinomatosis, spinal cord compression, untreated brain metastases or symptomatic or unstable brain metastases. Note: Patients with stable brain metastases (defined as asymptomatic or no requirement for high-dose [defined as dexamethasone 10 mg daily or higher] or increasing dose of systemic corticosteroids) and without imminent need of radiation therapy are eligible. If applicable, patients must have completed brain radiation therapy and recovered adequately from any associated toxicity and/or complications prior to eligibility assessment. For patients who have received prior radiation therapy, post-treatment MRI scan should show no increase in brain lesion size/volume.
   2. Unstable angina pectoris, symptomatic congestive heart failure (New York Heart Association, NYHA class III or IV), myocardial infarction ≤6 months prior to first study treatment, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease.
   3. Pre-existing severely impaired lung function. If a patient has a pre-existing pulmonary condition, eligible patients should have a spirometry and diffusing capacity for carbon monoxide (DLCO) that is >50% of the normal predicted value and/or O2 saturation that is >88% at rest on room air (Note: spirometry and pulmonary function tests [PFTs] not required to be performed unless clinically indicated).
   4. Nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy.
   5. A history of malignancies other than the one under treatment unless the patient is disease-free for more than 5 years from diagnosis. Note, controlled non-melanoma skin cancers, carcinoma in situ of the cervix, resected incidental prostate cancer, certain low grade hematologic malignancies (eg CLL, follicular lymphoma, etc), or other adequately treated carcinoma-in-situ may be eligible, after discussion with the medical monitor.
   6. Uncontrolled hypertension (systolic blood pressure ≥160 mm-Hg and/or diastolic blood pressure ≥100 mm Hg).
   7. Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension.
   8. Individuals with known human immunodeficiency virus (HIV) infection are excluded from this study as combination antiretroviral therapy could potentially result in significant pharmacokinetic interactions. In addition, these individuals are at increased risk of serious infections due to the immunosuppressive effects of mTOR inhibition.
   9. Active Hepatitis B or Hepatitis C, with detectable viral load.

5. Regarding concomitant medications with significant CYP3A4 and P-gp interactions, discontinuation of strong inhibitors (eg, ketoconazole, itraconazole, voriconazole, erythromycin, clarithromycin, telithromycin, and others), strong inducers (eg, rifampin, rifabutin), and known CYP3A4 substrates with a narrow therapeutic window (eg, fentanyl, alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, or terfenadine) is required at least 5 half lives prior to receiving the first dose of nab-sirolimus, whichever is longer.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm A: Pathogenic inactivating TSC1 alterations	nab-sirolimus	Patients with pathogenic inactivating TSC1 alterations.
Arm B: Pathogenic inactivating TSC2 alterations	nab-sirolimus	Patients with pathogenic inactivating TSC2 alterations.

Primary Outcome Measures

Name	Time	Method
Overall response rate (ORR)	9 months	ORR based on the proportion of patients with best overall response (BOR) of confirmed partial response (PR) or complete response (CR) from the time of study treatment initiation until disease progression as determined by IRR using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

Secondary Outcome Measures

Name	Time	Method
Overall survival	24 months	Number of months from study treatment initiation to the date of death due to any cause
Time to response	9 months	Time from first dose of study drug to initial measurement of CR or PR, where CR or PR is subsequently confirmed
Duration of response (DOR)	9 months	Determined for patients with BOR of confirmed CR or PR (by IRR)
Patient-reported outcome	9 months	Changes from baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire v3.0 (EORTC-QOQ-C30) scores
Incidence and severity of treatment-emergent and treatment-related adverse events (AEs)	9 months	Incidence and severity of treatment-emergent and treatment-related AEs as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0
Disease control rate	9 months	BOR of confirmed CR or PR (either of any duration) or stable disease (SD) following study treatment initiation (by IRR)
Progression-free survival	9 months	Number of months from study treatment initiation to the date of disease progression (by IRR) or death due to any cause

Trial Locations

Locations (119)

Morehouse School of Medicine; 🇺🇸 Atlanta, Georgia, United States

HOACNY; 🇺🇸 East Syracuse, New York, United States

Hematology Oncology Associates of Fredericksburg; 🇺🇸 Fredericksburg, Virginia, United States

Holy Cross Hospital; 🇺🇸 Fort Lauderdale, Florida, United States

Florida Cancer Specialists and Research Institute - North Division; 🇺🇸 Saint Petersburg, Florida, United States

Oncology Hematology Associates; 🇺🇸 Springfield, Missouri, United States

Aultman Medical Group; 🇺🇸 Canton, Ohio, United States

Spokane Urology; 🇺🇸 Spokane, Washington, United States

Seoul National University Hospital; 🇰🇷 Seoul, Korea, Republic of

Asan Medical Center; 🇰🇷 Seoul, Korea, Republic of

Pan Oncology Trials, LLC; 🇵🇷 San Juan, Puerto Rico

Nebraska Cancer Specialists; 🇺🇸 Grand Island, Nebraska, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Cleveland Clinic; 🇺🇸 Cleveland, Ohio, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

TriHealth; 🇺🇸 Cincinnati, Ohio, United States

Minnesota Oncology Hematology; 🇺🇸 Minneapolis, Minnesota, United States

OptumCare Cancer Care-Parent; 🇺🇸 Las Vegas, Nevada, United States

Comprehensive Cancer Centers of Nevada; 🇺🇸 Las Vegas, Nevada, United States

University of Cincinnati (UC) - Cancer Institute; 🇺🇸 Cincinnati, Ohio, United States

South Texas Accelerated Research Therapeutics (START); 🇺🇸 San Antonio, Texas, United States

Sanford Health-Fargo; 🇺🇸 Fargo, North Dakota, United States

Englewood Hospital and Medical Center; 🇺🇸 Englewood, New Jersey, United States

Utah Cancer Specialists; 🇺🇸 Salt Lake City, Utah, United States

UCSF Helen Diller Family Comprehensive Cancer Center; 🇺🇸 San Francisco, California, United States

Honor Health; 🇺🇸 Phoenix, Arizona, United States

Barbara Ann Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Oklahoma State University (OSU) - Stephenson Cancer Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Alabama Oncology; 🇺🇸 Birmingham, Alabama, United States

Arizona Oncology Associates; 🇺🇸 Irving, Texas, United States

Southern Cancer Center; 🇺🇸 Mobile, Alabama, United States

Yuma Regional Medical Center; 🇺🇸 Yuma, Arizona, United States

PCR Oncology; 🇺🇸 Arroyo Grande, California, United States

Nextgen Oncology; 🇺🇸 Beverly Hills, California, United States

Providence Medical Foundation (Fullerton); 🇺🇸 Fullerton, California, United States

City of Hope; 🇺🇸 Duarte, California, United States

USC Norris Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

UCLA - Jonsson Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

Providence Medical Foundation (Napa); 🇺🇸 Napa, California, United States

Ridley-Tree Cancer Center; 🇺🇸 Santa Barbara, California, United States

Providence Medical Foundation; 🇺🇸 Santa Rosa, California, United States

Stanford Cancer Center; 🇺🇸 Stanford, California, United States

Sarcoma Oncology Research Center; 🇺🇸 Santa Monica, California, United States

The Oncology Institute of Hope & Innovation; 🇺🇸 Whittier, California, United States

Rocky Mountain Cancer Centers; 🇺🇸 Thornton, Colorado, United States

Eastern Connecticut Hematology and Oncology; 🇺🇸 Norwich, Connecticut, United States

Hartford Healthcare; 🇺🇸 Hartford, Connecticut, United States

Florida Cancer Specialists - South Division; 🇺🇸 Venice, Florida, United States

Florida Cancer Specialists South Division; 🇺🇸 Fort Myers, Florida, United States

Cancer Specialist - East; 🇺🇸 Daytona Beach, Florida, United States

The Oncology Institute of Hope and Innovation; 🇺🇸 Lakeland, Florida, United States

Ocala Oncology; 🇺🇸 Ocala, Florida, United States

Florida Cancer Specialists - South; 🇺🇸 Fort Myers, Florida, United States

Cancer Specialists of North Florida; 🇺🇸 Jacksonville, Florida, United States

TOI Florida; 🇺🇸 Lakeland, Florida, United States

Florida Cancer Specialists - North; 🇺🇸 Saint Petersburg, Florida, United States

Hope and Healing Cancer Services; 🇺🇸 Hinsdale, Illinois, United States

Florida Cancer Specialists - East; 🇺🇸 West Palm Beach, Florida, United States

Florida Cancer Specialist - East; 🇺🇸 Stuart, Florida, United States

Northwest Oncology and Hematology; 🇺🇸 Rolling Meadows, Illinois, United States

Urology of Indiana; 🇺🇸 Carmel, Indiana, United States

Our Lady of the Lake; 🇺🇸 Baton Rouge, Louisiana, United States

Fort Wayne Medical Oncology and Hematology; 🇺🇸 Fort Wayne, Indiana, United States

Goshen Health; 🇺🇸 Goshen, Indiana, United States

Pontchartrain; 🇺🇸 Hammond, Louisiana, United States

Frederick Health; 🇺🇸 Frederick, Maryland, United States

Maryland Oncology Hematology; 🇺🇸 Rockville, Maryland, United States

Southcoast Centers for Cancer Care; 🇺🇸 Fairhaven, Massachusetts, United States

Central Care Cancer Center; 🇺🇸 Bolivar, Missouri, United States

Sparrow Hospital; 🇺🇸 Lansing, Michigan, United States

Lake Regional; 🇺🇸 Osage Beach, Missouri, United States

Mosaic Life Care; 🇺🇸 Saint Joseph, Missouri, United States

New Jersey Cancer Care and Blood Disorders; 🇺🇸 Belleville, New Jersey, United States

Summit Medical Group - NJ; 🇺🇸 Florham Park, New Jersey, United States

Roswell Park Comprehensive Cancer Center; 🇺🇸 Buffalo, New York, United States

Atlantic Health System - Morristown Medical Center; 🇺🇸 Morristown, New Jersey, United States

David H. Koch Center for Cancer Care at Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

Cayuga Medical Center; 🇺🇸 Ithaca, New York, United States

Southeastern Medical Oncology; 🇺🇸 Goldsboro, North Carolina, United States

The Toledo Clinic; 🇺🇸 Toledo, Ohio, United States

Oklahoma Cancer Specialist; 🇺🇸 Tulsa, Oklahoma, United States

Gettysburg-PCSRI; 🇺🇸 Gettysburg, Pennsylvania, United States

Cancer Care Associates of York - Parent; 🇺🇸 York, Pennsylvania, United States

Prisma Health Cancer Institute; 🇺🇸 Greenville, South Carolina, United States

Alliance Cancer Specialists; 🇺🇸 Langhorne, Pennsylvania, United States

Avera Cancer Institute; 🇺🇸 Sioux Falls, South Dakota, United States

Sanford Health; 🇺🇸 Sioux Falls, South Dakota, United States

Sarah Cannon and HCA Research Institute; 🇺🇸 Smyrna, Tennessee, United States

Baptist Cancer Center; 🇺🇸 Memphis, Tennessee, United States

West Cancer Center; 🇺🇸 Germantown, Tennessee, United States

Mary Crowley Cancer Research; 🇺🇸 Dallas, Texas, United States

Texas Oncology - DFW; 🇺🇸 Dallas, Texas, United States

Texas Oncology; 🇺🇸 Tyler, Texas, United States

Oncology Consultants; 🇺🇸 Houston, Texas, United States

Lumi Research; 🇺🇸 Kingwood, Texas, United States

Community Cancer Trials of Utah; 🇺🇸 Ogden, Utah, United States

Texas Oncology Central-South; 🇺🇸 McAllen, Texas, United States

University of Washington Cancer Consortium; 🇺🇸 Seattle, Washington, United States

Virginia Cancer Specialists; 🇺🇸 Fairfax, Virginia, United States

Northwest Medical Specialties; 🇺🇸 Tacoma, Washington, United States

Inje University Haeundae Paik Hospital; 🇰🇷 Busan, Korea, Republic of

ThedaCare; 🇺🇸 Appleton, Wisconsin, United States

Cancer Care Northwest; 🇺🇸 Spokane, Washington, United States

Gunderson Health System; 🇺🇸 La Crosse, Wisconsin, United States

Severance Hospital, Yonsei University Health System; 🇰🇷 Seoul, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

Korea University Guro Hospital; 🇰🇷 Seoul, Korea, Republic of

Hoag Memorial Hospital Presbyterian; 🇺🇸 Newport Beach, California, United States

MemorialCare; 🇺🇸 Long Beach, California, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

Rocky Mountain Cancer Centers (Williams St); 🇺🇸 Denver, Colorado, United States

American Oncology Partners of Maryland PA (Center for Cancer & Blood Disorders); 🇺🇸 Bethesda, Maryland, United States

Nebraska Methodist Hospital; 🇺🇸 Omaha, Nebraska, United States

Florida Cancer Specialists - North Division; 🇺🇸 Trinity, Florida, United States

Hawaii Cancer Center; 🇺🇸 Honolulu, Hawaii, United States

Virginia Urology; 🇺🇸 Richmond, Virginia, United States

University of Wisconsin - Carbone Cancer Center; 🇺🇸 Madison, Wisconsin, United States

Thomas Jefferson University; 🇺🇸 Philadelphia, Pennsylvania, United States

Sharp HealthCare; 🇺🇸 San Diego, California, United States