A Phase 2 Study of Nab-sirolimus (ABI-009) in Patients With Advanced Malignant PEComa

Study Overview
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Brief Summary
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A phase 2 multi-center investigation of efficacy of nab-sirolimus (formerly known as ABI-009 or nab-rapamycin) in patients with advanced malignant perivascular epithelioid cell tumor (PEComa).

Detailed Description
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This was a phase 2, single-arm, open-label, multi-center study to determine the efficacy and safety profile of nab-sirolimus in patients with advanced malignant PEComa. Patients were required to have measurable disease at baseline (per RECIST v1.1). Eligible patients received nab-sirolimus at 100 mg/m2 by IV infusion (over 30 minutes) weekly for 2 weeks followed by a week of rest (ie, on Day 1 and Day 8 in 21-day cycles). Patients remained on treatment until they experienced progressive disease or unacceptable toxicity, withdrew consent, or physician's decision. Patients who discontinued treatment entered the on-study Follow-up period for survival. Computed tomography or magnetic resonance imaging (MRI) scans were performed at screening, every 6 weeks for the first year, then every 12 weeks thereafter until the end of treatment. Throughout treatment with nab-sirolimus, patients were routinely assessed for toxicities, the need for dose modifications, and response assessments. The sample size was targeted to be  30 patients in order to provide a reasonably precise estimate of the true ORR. Assuming an observed ORR of 30% and a sample size of 30, the lower bound of the 95% confidence interval (CI) for the estimated ORR would exclude values less than 14.7%. The primary analysis was predefined to be conducted when all patients have had the opportunity to be treated for at least 6 months. The study remained open for 3 additional years and the final analysis occured at study closure.

Official Title
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A Phase 2 Multi-center Investigation of Efficacy of ABI-009 (Nab-sirolimus) in Patients With Advanced Malignant Perivascular Epithelioid Cell Tumors (PEComa)

Conditions
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Malignant PEComa

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 histologically confirmed diagnosis of malignant PEComa that is either metastatic or locally advanced and for which surgery is not a recommended option. Patients must have available tumor block along with the corresponding pathology report (or approximately 30 unstained slides, with a minimum of 16 slides), and/or fresh biopsy to allow retrospective centralized confirmation of malignant PEComa and for mTOR pathway analysis and biomarker analysis. Patients must have one or more measurable target lesions by CT scan or MRI. Measurable disease by RECIST v1.1. Patients must not have been previously treated with an mTOR inhibitor. Prior treatment (investigational or other), chemotherapy, radiotherapy, surgery, or other therapeutic agents (except mTOR inhibitors) is allowed, if completed after 5 half-lives or ≥28 days prior to enrollment, whichever is shorter. Eligible patients, 18 years or older, with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Patients must have the following blood chemistry levels at screening (obtained ≤14 days prior to enrollment (local laboratory): total bilirubin ≤1.5 x upper limit of normal (ULN) mg/dl AST ≤2.5 x ULN (≤5 x ULN if attributable to liver metastases) serum creatinine ≤1.5 x ULN Adequate biological parameters as demonstrated by the following blood counts at screening (obtained ≤14 days prior to enrollment, local laboratory): Absolute neutrophil count (ANC) ≥1.5 × 109/L; Platelet count ≥100,000/mm3 (100 × 109/L); Hemoglobin ≥9 g/dL. Serum triglyceride <300 mg/dL; serum cholesterol < 350 mg/dL. Male or non-pregnant and non-breast feeding female: Females of child-bearing potential must agree to use effective contraception without interruption from 28 days prior to starting IP and while on study medication and have a negative serum pregnancy test (β -hCG) result at screening and agree to ongoing pregnancy testing during the course of the study, and after the end of study treatment. Male patients 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, even if he has undergone a successful vasectomy. Life expectancy of >3 months, as determined by the investigator. Ability to understand and sign informed consent. Willingness and ability to comply with scheduled visits, laboratory tests, and other study procedures. Exclusion Criteria: A patient will not be eligible for inclusion in this study if any of the following criteria apply: Patients with lymphangioleiomyomatosis (LAM) are excluded. Known active uncontrolled or symptomatic central nervous system (CNS) metastases. A patient with controlled and asymptomatic CNS metastases may participate in this study. As such, the patient must have completed any prior treatment for CNS metastases ≥28 days (including radiotherapy and/or surgery) prior to start of treatment in this study and should not be receiving chronic corticosteroid therapy for the CNS metastases. Active gastrointestinal bleeding, if transfusion dependent. Pre-existing thyroid abnormality is allowed provided thyroid function can be controlled with medication. Uncontrolled serious medical or psychiatric illness. Patients with a currently active second malignancy other than non-melanoma skin cancers, carcinoma in situ of the cervix, resected incidental prostate cancer (staged pT2 with Gleason Score ≤ 6 and postoperative PSA <0.5 ng/mL), or other adequately treated carcinoma-in-situ are ineligible. Patients are not considered to have a currently active malignancy if they have completed therapy and are free of disease for ≥1 year). Liver-directed therapy within 2 months of enrollment. Prior treatment with radiotherapy (including radio-labeled spheres and/or cyberknife, hepatic arterial embolization (with or without chemotherapy) or cyrotherapy/ablation) is allowed if these therapies did not affect the areas of measurable disease being used for this protocol. Recent infection requiring systemic anti-infective treatment that was completed ≤14 days prior to enrollment (with the exception of uncomplicated urinary tract infection or upper respiratory tract infection). Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. Unstable coronary artery disease or myocardial infarction during preceding 6 months. Receiving any concomitant antitumor therapy. Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension. The use of certain medications and illicit drugs within 5 half-lives or 28 days, whichever is shorter prior to the first dose of study drug and for the duration of the study will not be allowed. Use of strong inhibitors and inducers of CYP3A4 within the 14 days prior to receiving the first dose of ABI-009. Additionally, use of any known CYP3A4 substrates with narrow therapeutic window (such as fentanyl, alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, terfanide) within the 14 days prior to receiving the first dose of ABI-009.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: nab-Sirolimus<br>Patients with malignant PEComa received nab-sirolimus on Days 1 and 8 of every 21-day cycle, as a 30-minute IV infusion. | Drug: nab-Sirolimus<br>* Patients received nab-sirolimus at 100 mg/m2 on Days 1 and 8 of a 21-day cycle by intravenous infusion over 30 minutes.<br>* Other names: nab-rapamycin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Overall Response Rate (ORR) | Best ORR was assessed by Independent Radiology Review using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Criteria. Best overall response was the best response recorded from the start of the study treatment until the end of treatment taking into account the requirement for confirmation. Per RECIST v1.1, best overall response assignment depended on the findings of both target and non-target disease and also took into consideration the appearance of new lesions. Overall response rate was defined as the percentage of patients who achieve a confirmed PR or CR per RECIST 1.1. At each timepoint, objective tumor response for target lesions were assessed as such: Complete Response (CR), disappearance of all target lesions, and pathological lymph nodes must have a reduction <10 mm; Partial Response (PR), ≥30% decrease in the sum of the longest diameter of target lesions. | through study completion (up to 72 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | The time from the start of CR or PR to the first date of documented PD or death. | From Initial response until tumor progression, through study completion (up to 72 months) | 
| Progression-free Survival Rate at 6 Months | The time from the first dose date to the first observation of a disease progression or death due to any cause by 6 mo. Disease progression was assessed radiologically per RECIST v1.1, and was defined as ≥20% increase in the sum of diameters of target lesions, and absolute increase of ≥5 mm. PFS rate at 6 months was summarized using Kaplan-Meier methods (percentage rounded up to 1 digit decimal). | 6 months | 
| Progression-free Survival (Median) | The time from the first dose date to the first observation of a disease progression or death due to any cause. | from start of treatment to first documented disease progression, through study completion (up to 72 months) | 
| Overall Survival | Defined as teh time from first dose date to the date of death due to any cause | From start of treatment to date of death (of any cause), through study completion (up to 72 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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malignant PEComa, perivascular epithelioid cell tumors