Nivolumab (Opdivo®) Plus ABI-009 (Nab-rapamycin) for Advanced Sarcoma and Certain Cancers

Study Overview
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Brief Summary
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This study investigates the safety/toxicity and potential anti-tumor activity of sequential administration of nivolumab and escalating doses of the mTOR inhibitor ABI-009 in advanced Ewing's sarcoma, PEComa, epithelioid sarcoma, desmoid tumor, chordoma, non-small cell lung cancer, small cell lung cancer, urethelial carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma of head and neck, hepatocellular carcinoma, classical Hodgkin's lymphoma, MSI-H/dMMR metastatic colorectal cancer, and tumors with genetic mutations sensitive to mTOR inhibitors

Detailed Description
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The primary objective of this study is to investigate the maximum tolerated dose of ABI-009, an mTOR inhibitor, when given sequentially with nivolumab in advanced Ewing's sarcoma, PEComa, epithelioid sarcoma, desmoid tumor, chordoma, non-small cell lung cancer, small cell lung cancer, urethelial carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma of head and neck, hepatocellular carcinoma, classical Hodgkin's lymphoma, MSI-H/dMMR metastatic colorectal cancer, and tumors with genetic mutations sensitive to mTOR inhibitors The secondary objectives are to investigate the disease control rate (DCR) and progression free survival (PFS) using nivolumab/ABI-009 combination therapy in advanced Ewing's sarcoma, PEComa, epithelioid sarcoma, desmoid tumor, chordoma, non-small cell lung cancer, small cell lung cancer, urethelial carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma of head and neck, hepatocellular carcinoma, classical Hodgkin's lymphoma, MSI-H/dMMR metastatic colorectal cancer, and tumors with genetic mutations sensitive to mTOR inhibitors The exploratory objectives are (1) To correlate progression free survival (PFS) based on Immune-related Response Criteria (irRECIST) with that based on RECIST v1.1, and (2) To correlate PFS with PD-1 and PD-L1 expression in patients' tumors.

Official Title
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A Phase 1/2 Study Using Nivolumab and ABI-009 for Advanced Sarcoma, Advanced Carcinoma Treated With PD1 Inhibitors, and Tumors With Genetic Mutations Sensitive to mTOR Inhibitors

Conditions
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Ewing Sarcoma, PEComa, Epithelioid Sarcoma, Desmoid Tumor, Chordoma, Non Small Cell Lung Cancer, Urothelial Carcinoma, Melanoma, Renal Cell Carcinoma, Squamous Cell Carcinoma, Hepatocellular Carcinoma, Classical Hodgkin Lymphoma, Colorectal Cancer, MTOR Activating Mutation

Intervention / Treatment
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* Drug: Nab-Rapamycin
* Biological: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A patient will be eligible for inclusion in this study only if all of the following criteria are met: Patients must have a histologically confirmed diagnosis of Ewing's sarcoma, PEComa, epithelioid sarcoma, desmoid tumor, chordoma, non-small cell lung cancer, small cell lung cancer, urethelial carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma of head and neck, hepatocellular carcinoma, classical Hodgkin's lymphoma, MSI-H/dMMR metastatic colorectal cancer, and tumors with genetic mutations sensitive to mTOR inhibitors, that is either metastatic or locally advanced and for which surgery is not a recommended option. 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 a PD-1 inhibitor in combination with an mTOR inhibitor. Prior treatment (investigational or other), chemotherapy, radiotherapy, surgery, or other therapeutic agents (except immunotherapy and mTOR inhibitors) is allowed, if completed after 5 half-lives or ≥28 days prior to enrollment, whichever is shorter. Eligible patients, 12 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 xprior 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. A second form of birth control is required even if she has had a tubal ligation. 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. A second form of birth control is required 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: Concurrent or prior immunotherapy with a PD-1 inhibitor in combination with an mTOr inhibitor. 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. 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. 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. Known Human Immunodeficiency Virus (HIV). Active Hepatitis B or Hepatitis C. Non-oncology vaccine therapy used for prevention of infectious disease within 4 weeks of trial enrollment Autoimmune disease including rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis and motor neuropathy considered to be of autoimmune origin (e.g. Guillain-Barre Syndrome) Systemic immunosuppression, including HIV positive status with or without AIDS Skin rash (psoriasis, eczema) affecting > 25% body surface area Inflammatory bowel disease (Crohn's or ulcerative colitis) Ongoing or uncontrolled diarrhea within 4 weeks of trial enrollment Recent history of acute diverticulitis, intraabdominal abscess or gastrointestinal obstruction within 6 months of trial enrollment, which are known risk factors for bowel perforation Current, active or previous history of heavy alcohol abuse Pituitary endocrinopathy Adrenal insufficiency or excess

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>This is an open label, dose-seeking phase 1b study using a defined dose of nivolumab and escalating doses of Nab-Rapamycin (ABI-009) given intravenously. I. Dose Escalation Phase 1 Part of Study: The study will employ the standard cohort of three design. No intra-patient dose escalation will take place. II. Expansion Phase 1b Part of Study: Following dose escalation, an additional 22-28 patients will receive ABI-009 at the MTD and defined doses of nivolumab to assess overall safety and potential efficacy in a greater number of patients. Patients in the expansion phase of the study may continue treatment up to 18 three-week cycles or until significant disease progression or unacceptable toxicity occurs. | Drug: Nab-Rapamycin<br>* Escalating doses of ABI-009 will be given IV over 30 min for 2 of every 3 weeks beginning Day 8 Cycle 2. Only nivolumab will be given in Cycle 1. At Dose Level 1, 3-6 patients will receive 56 mg/m2; at Dose Level 2, 3-6 six patients will receive 75 mg/m2; and at Dose Level 3, 3-6 patients will receive 100 mg/m2.<br>* Other names: ABI-009;Biological: Nivolumab<br>* A defined dose of nivolumab, 3 mg/kg, will be given IV over 30 minutes q 3 weeks<br>* Other names: Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose | Dose escalation study, determination of maximum tolerated dose (MTD) in previously treated patients with soft tissue sarcoma | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate | Effect of dual therapy with ABI-009 and nivolumab on Disease Control Rate in advanced soft tissue sarcoma | 24 months | 
| Progression free survival | Effect of dual therapy with ABI-009 and nivolumab on progression free survival (PFS) | 24 months | 
| Overall survival | Effect of dual therapy with ABI-009 and nivolumab on overall survival in advanced soft tissue sarcoma | 24 months |