Clinical trial NCT05103358: Phase 2 Basket Trial of Nab-sirolimus in Patients With Malignant Solid Tumors With Pathogenic Alterations in TSC1/TSC2 Genes (PRECISION 1)
Official title: 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.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Tumor
Tumor, Solid
Metastasis
Metastatic Cancer
Cancer
Cancer Metastatic
Tumors
Neoplasms
Neoplasm Metastasis
Solid Tumor
Advanced Solid Tumor
Advanced Cancer
Malignant Solid Tumor
Malignant Solid Neoplasm
Malignant Neoplasm
Malignant Tumor
TSC
TSC1
TSC2
Metastatic Solid Tumor
Metastatic Neoplasm
Keywords: TSC1 gene
TSC2 gene
Tissue agnostic
Basket
nab-sirolimus
mTOR inhibitor
nanoparticle albumin bound
mammalian target of rapamycin
mechanistic target of rapamycin
tumor profile
tuberous sclerosis complex 1
tuberous sclerosis complex 2
mTOR
sirolimus
TSC1
TSC2
ABI-009
FYARRO
Precision
Precision 1
Pathogenic alterations
Pathogenic mutations
Inactivating mutations
Lead sponsor: Aadi Bioscience, Inc.
Sponsor class: INDUSTRY
First posted: 2021-11-02
Enrollment: 120
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall response rate (ORR)
timeFrame: 9 months
Secondary outcomes:
measure: Duration of response (DOR)
timeFrame: 9 months
measure: Disease control rate
timeFrame: 9 months
measure: Time to response
timeFrame: 9 months
measure: Progression-free survival
timeFrame: 9 months
measure: Overall survival
timeFrame: 24 months
measure: Patient-reported outcome
timeFrame: 9 months
measure: Incidence and severity of treatment-emergent and treatment-related adverse events (AEs)
timeFrame: 9 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Oncology
state: Alabama
city: Mobile
country: United States
facility: Southern Cancer Center
state: Alabama
city: Goodyear
country: United States
facility: Arizona Oncology Associates
state: Arizona
city: Phoenix
country: United States
facility: Honor Health
state: Arizona
city: Prescott Valley
country: United States
facility: Arizona Oncology Associates
state: Arizona
city: Yuma
country: United States
facility: Yuma Regional Medical Center
state: Arizona
city: Arroyo Grande
country: United States
facility: PCR Oncology
state: California
city: Beverly Hills
country: United States
facility: Nextgen Oncology
state: California
city: Duarte
country: United States
facility: City of Hope
state: California
city: Fullerton
country: United States
facility: Providence Medical Foundation (Fullerton)
state: California
city: Long Beach
country: United States
facility: MemorialCare
state: California
city: Los Angeles
country: United States
facility: USC Norris Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA - Jonsson Comprehensive Cancer Center
state: California
city: Napa
country: United States
facility: Providence Medical Foundation (Napa)
state: California
city: Newport Beach
country: United States
facility: Hoag Memorial Hospital Presbyterian
state: California
city: San Diego
country: United States
facility: Sharp HealthCare
state: California
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Santa Barbara
country: United States
facility: Ridley-Tree Cancer Center
state: California
city: Santa Monica
country: United States
facility: Sarcoma Oncology Research Center
state: California
city: Santa Rosa
country: United States
facility: Providence Medical Foundation
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center
state: California
city: Whittier
country: United States
facility: The Oncology Institute of Hope & Innovation
state: California
city: Aurora
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Boulder
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Colorado Springs
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers (Williams St)
state: Colorado
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Lakewood
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Littleton
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Lone Tree
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Longmont
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Pueblo
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Thornton
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Hartford
country: United States
facility: Hartford Healthcare
state: Connecticut
city: Norwich
country: United States
facility: Eastern Connecticut Hematology and Oncology
state: Connecticut
city: Altamonte Springs
country: United States
facility: Florida Cancer Specialists - North Division
state: Florida
city: Bonita Springs
country: United States
facility: Florida Cancer Specialists - South Division
state: Florida
city: Bradenton
country: United States
facility: Florida Cancer Specialists - South Division
state: Florida
city: Bradenton
country: United States
facility: Florida Cancer Specialists - South Division
state: Florida
city: Brandon
country: United States
facility: Florida Cancer Specialists - North Division
state: Florida
city: Cape Coral
country: United States
facility: Florida Cancer Specialists - South Division
state: Florida
city: Clearwater
country: United States
facility: Florida Cancer Specialists - North Division
state: Florida
city: Daytona Beach
country: United States
facility: Cancer Specialist - East
state: Florida
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital
state: Florida
city: Fort Myers
country: United States
facility: Florida Cancer Specialists South Division
state: Florida
city: Fort Myers
country: United States
facility: Florida Cancer Specialists - South
state: Florida
city: Fort Myers
country: United States
facility: Florida Cancer Specialists - South
state: Florida
city: Gainesville
country: United States
facility: Florida Cancer Specialists - North Division
state: Florida
city: Jacksonville
country: United States
facility: Cancer Specialists of North Florida
state: Florida
city: Lakeland
country: United States
facility: The Oncology Institute of Hope and Innovation
state: Florida
city: Lakeland
country: United States
facility: TOI Florida
state: Florida
city: Largo
country: United States
facility: Florida Cancer Specialists - North Division
state: Florida
city: Lecanto
country: United States
facility: Florida Cancer Specialists - North Division
state: Florida
city: Naples
country: United States
facility: Florida Cancer Specialists - South Division
state: Florida
city: Ocala
country: United States
facility: Florida Cancer Specialists - North Division
state: Florida
city: Ocala
country: United States
facility: Ocala Oncology
state: Florida
city: Orange City
country: United States
facility: Florida Cancer Specialists - North Division
state: Florida
city: Orlando
country: United States
facility: Florida Cancer Specialists - North Division
state: Florida
city: Port Charlotte
country: United States
facility: Florida Cancer Specialists - South Division
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialists and Research Institute - North Division
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialists - North
state: Florida
city: Sarasota
country: United States
facility: Florida Cancer Specialists - South Division
state: Florida
city: Sarasota
country: United States
facility: Florida Cancer Specialists - South Division
state: Florida
city: Stuart
country: United States
facility: Florida Cancer Specialist - East
state: Florida
city: Tampa
country: United States
facility: Florida Cancer Specialists - North Division
state: Florida
city: Tavares
country: United States
facility: Florida Cancer Specialists - North Division
state: Florida
city: Trinity
country: United States
facility: Florida Cancer Specialists - North Division
state: Florida
city: Venice
country: United States
facility: Florida Cancer Specialists - South Division
state: Florida
city: Venice
country: United States
facility: Florida Cancer Specialists - South Division
state: Florida
city: Vero Beach
country: United States
facility: Florida Cancer Specialists - East
state: Florida
city: Wellington
country: United States
facility: Florida Cancer Specialists - East
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists - East
state: Florida
city: Atlanta
country: United States
facility: Morehouse School of Medicine
state: Georgia
city: Honolulu
country: United States
facility: Hawaii Cancer Center
state: Hawaii
city: Hinsdale
country: United States
facility: Hope and Healing Cancer Services
state: Illinois
city: Rolling Meadows
country: United States
facility: Northwest Oncology and Hematology
state: Illinois
city: Carmel
country: United States
facility: Urology of Indiana
state: Indiana
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology
state: Indiana
city: Goshen
country: United States
facility: Goshen Health
state: Indiana
city: Baton Rouge
country: United States
facility: Our Lady of the Lake
state: Louisiana
city: Hammond
country: United States
facility: Pontchartrain
state: Louisiana
city: Bethesda
country: United States
facility: American Oncology Partners of Maryland PA (Center for Cancer & Blood Disorders)
state: Maryland
city: Frederick
country: United States
facility: Frederick Health
state: Maryland
city: Rockville
country: United States
facility: Maryland Oncology Hematology
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Fairhaven
country: United States
facility: Southcoast Centers for Cancer Care
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Lansing
country: United States
facility: Sparrow Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Minnesota Oncology Hematology
state: Minnesota
city: Bolivar
country: United States
facility: Central Care Cancer Center
state: Missouri
city: Osage Beach
country: United States
facility: Lake Regional
state: Missouri
city: Saint Joseph
country: United States
facility: Mosaic Life Care
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Springfield
country: United States
facility: Oncology Hematology Associates
state: Missouri
city: Grand Island
country: United States
facility: Nebraska Cancer Specialists
state: Nebraska
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: Las Vegas
country: United States
facility: OptumCare Cancer Care-Parent
state: Nevada
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Belleville
country: United States
facility: New Jersey Cancer Care and Blood Disorders
state: New Jersey
city: Englewood
country: United States
facility: Englewood Hospital and Medical Center
state: New Jersey
city: Florham Park
country: United States
facility: Summit Medical Group - NJ
state: New Jersey
city: Morristown
country: United States
facility: Atlantic Health System - Morristown Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: East Syracuse
country: United States
facility: HOACNY
state: New York
city: Ithaca
country: United States
facility: Cayuga Medical Center
state: New York
city: New York
country: United States
facility: David H. Koch Center for Cancer Care at Memorial Sloan Kettering Cancer Center
state: New York
city: Goldsboro
country: United States
facility: Southeastern Medical Oncology
state: North Carolina
city: Fargo
country: United States
facility: Sanford Health-Fargo
state: North Dakota
city: Canton
country: United States
facility: Aultman Medical Group
state: Ohio
city: Cincinnati
country: United States
facility: TriHealth
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati (UC) - Cancer Institute
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Toledo
country: United States
facility: The Toledo Clinic
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma State University (OSU) - Stephenson Cancer Center
state: Oklahoma
city: Tulsa
country: United States
facility: Oklahoma Cancer Specialist
state: Oklahoma
city: Gettysburg
country: United States
facility: Gettysburg-PCSRI
state: Pennsylvania
city: Langhorne
country: United States
facility: Alliance Cancer Specialists
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: York
country: United States
facility: Cancer Care Associates of York - Parent
state: Pennsylvania
city: Greenville
country: United States
facility: Prisma Health Cancer Institute
state: South Carolina
city: Sioux Falls
country: United States
facility: Avera Cancer Institute
state: South Dakota
city: Sioux Falls
country: United States
facility: Sanford Health
state: South Dakota
city: Dickson
country: United States
facility: Sarah Cannon and HCA Research Institute
state: Tennessee
city: Franklin
country: United States
facility: Sarah Cannon and HCA Research Institute
state: Tennessee
city: Gallatin
country: United States
facility: Sarah Cannon and HCA Research Institute
state: Tennessee
city: Germantown
country: United States
facility: West Cancer Center
state: Tennessee
city: Henderson
country: United States
facility: Sarah Cannon and HCA Research Institute
state: Tennessee
city: Hermitage
country: United States
facility: Sarah Cannon and HCA Research Institute
state: Tennessee
city: Lebanon
country: United States
facility: Sarah Cannon and HCA Research Institute
state: Tennessee
city: Memphis
country: United States
facility: Baptist Cancer Center
state: Tennessee
city: Murfreesboro
country: United States
facility: Sarah Cannon and HCA Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon and HCA Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon and HCA Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon and HCA Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon and HCA Research Institute
state: Tennessee
city: Shelbyville
country: United States
facility: Sarah Cannon and HCA Research Institute
state: Tennessee
city: Smyrna
country: United States
facility: Sarah Cannon and HCA Research Institute
state: Tennessee
city: Dallas
country: United States
facility: Mary Crowley Cancer Research
state: Texas
city: Dallas
country: United States
facility: Texas Oncology - DFW
state: Texas
city: El Paso
country: United States
facility: Texas Oncology
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: Oncology Consultants
state: Texas
city: Irving
country: United States
facility: Arizona Oncology Associates
state: Texas
city: Kingwood
country: United States
facility: Lumi Research
state: Texas
city: McAllen
country: United States
facility: Texas Oncology Central-South
state: Texas
city: San Antonio
country: United States
facility: South Texas Accelerated Research Therapeutics (START)
state: Texas
city: Tyler
country: United States
facility: Texas Oncology
state: Texas
city: Ogden
country: United States
facility: Community Cancer Trials of Utah
state: Utah
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists
state: Utah
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Fredericksburg
country: United States
facility: Hematology Oncology Associates of Fredericksburg
state: Virginia
city: Richmond
country: United States
facility: Virginia Urology
state: Virginia
city: Seattle
country: United States
facility: University of Washington Cancer Consortium
state: Washington
city: Spokane
country: United States
facility: Spokane Urology
state: Washington
city: Spokane
country: United States
facility: Cancer Care Northwest
state: Washington
city: Tacoma
country: United States
facility: Northwest Medical Specialties
state: Washington
city: Appleton
country: United States
facility: ThedaCare
state: Wisconsin
city: La Crosse
country: United States
facility: Gunderson Health System
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin - Carbone Cancer Center
state: Wisconsin
city: Busan
country: Korea, Republic of
facility: Inje University Haeundae Paik Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: San Juan
country: Puerto Rico
facility: Pan Oncology Trials, LLC
Study officials:
References: