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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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.

Conditions
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Advanced Cancer, Tumor, Tumor, Solid, Metastasis, Metastatic Cancer, Cancer, Cancer Metastatic, Tumors, Neoplasms, Neoplasm Metastasis, Solid Tumor, Advanced Solid Tumor, Malignant Solid Tumor, Malignant Solid Neoplasm, Malignant Neoplasm, Malignant Tumor, TSC, TSC1, TSC2, Metastatic Solid Tumor, Metastatic Neoplasm

Intervention / Treatment
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* Drug: nab-sirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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. 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. Patients must have 1 or more measurable target lesions by computed tomography (CT) scan or magnetic resonance imaging (MRI) (RECIST v1.1). Age: 12 years or older. 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. Adequate liver function: Total bilirubin ≤1.5 × upper limit of normal (ULN) (unless due to Gilbert's syndrome, then ≤3 × ULN) Aspartate aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN if attributable to liver metastases) Adequate renal function: creatinine clearance ≥30 mL/min, Cockcroft-Gault CCr = ((140-age) × weight[kg]) / (72 × SCr[mL/min]) × 0.85, if female Adequate hematologic parameters: Absolute neutrophil count (ANC) ≥1.0 × 109/L (growth factor support allowed) Platelet count ≥100,000/mm3 (100 × 109/L) (transfusion and/or growth factor support allowed) Hemoglobin ≥8.0 g/dL (transfusion and/or growth factor support allowed) Fasting serum triglyceride must be ≤300 mg/dL; fasting serum cholesterol must be ≤350 mg/dL. 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. Male or non-pregnant and non-breastfeeding female: 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. 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. The patient or the patient's parent(s) or legal guardian(s) understand(s) and sign(s) the informed consent. Willingness and ability to comply with scheduled visits, laboratory tests, and other study procedures. Exclusion Criteria: Prior treatment with an mTOR inhibitor, including nab-sirolimus. Severe (Grade ≥3) ongoing infection requiring parenteral or oral anti-infective treatment, either ongoing or completed ≤7 days prior to enrollment. Patients with primary brain tumors or PEComa. Patients who have any severe and/or uncontrolled medical or psychiatric conditions or other conditions that could affect their participation including: 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. 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. 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). Nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy. 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. Uncontrolled hypertension (systolic blood pressure ≥160 mm-Hg and/or diastolic blood pressure ≥100 mm Hg). Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension. 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. Active Hepatitis B or Hepatitis C, with detectable viral load. 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.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Pathogenic inactivating TSC1 alterations<br>Patients with pathogenic inactivating TSC1 alterations. | Drug: nab-sirolimus<br>* Prospective phase 2, open-label, multi-institutional basket trial to determine the efficacy and safety of nab-sirolimus administered by IV infusion to patients<br>* Other names: ABI-009;|
| Experimental: Arm B: Pathogenic inactivating TSC2 alterations<br>Patients with pathogenic inactivating TSC2 alterations. | Drug: nab-sirolimus<br>* Prospective phase 2, open-label, multi-institutional basket trial to determine the efficacy and safety of nab-sirolimus administered by IV infusion to patients<br>* Other names: ABI-009;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | 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 | 9 months | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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