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

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ClinicalTrials.gov Identifier: NCT03190174
Recruitment Status : Recruiting
First Posted : June 16, 2017
Last Update Posted : September 6, 2018
Sponsor:
Collaborator:
Aadi, LLC
Information provided by (Responsible Party):
Sarcoma Oncology Research Center, LLC

Brief Summary:
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 UPS, LPS, CS, OS and Ewing sarcoma.

Condition or disease Intervention/treatment Phase
Undifferentiated Pleomorphic Sarcoma Liposarcoma Chondrosarcoma Osteosarcoma Ewing Sarcoma Drug: Nab-Rapamycin Biological: Nivolumab Phase 1 Phase 2

Detailed Description:

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 UPS, LPS, CS, OS and Ewing sarcoma.

The secondary objectives are to investigate the disease control rate (DCR) and progression free survival (PFS) using nivolumab/ABI-009 combination therapy in advanced UPS, LPS, CS, OS and Ewing sarcoma.

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Single Center Investigation of Safety/Efficacy of Nivolumab (Opdivo®) and ABI-009 (Nab-rapamycin) in Patients With Advanced Undifferentiated Pleomorphic Sarcoma, Liposarcoma, Chondrosarcoma, Osteosarcoma and Ewing Sarcoma
Actual Study Start Date : August 24, 2017
Estimated Primary Completion Date : February 1, 2020
Estimated Study Completion Date : April 1, 2020


Arm Intervention/treatment
Experimental: Arm 1

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
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.
Other Name: ABI-009

Biological: Nivolumab
A defined dose of nivolumab, 3 mg/kg, will be given IV over 30 minutes q 3 weeks
Other Name: Opdivo




Primary Outcome Measures :
  1. Maximum tolerated dose [ Time Frame: 6 months ]
    Dose escalation study, determination of maximum tolerated dose (MTD) in previously treated patients with soft tissue sarcoma


Secondary Outcome Measures :
  1. Disease control rate [ Time Frame: 24 months ]
    Effect of dual therapy with ABI-009 and nivolumab on Disease Control Rate in advanced soft tissue sarcoma

  2. Progression free survival [ Time Frame: 24 months ]
    Effect of dual therapy with ABI-009 and nivolumab on progression free survival (PFS)

  3. Overall survival [ Time Frame: 24 months ]
    Effect of dual therapy with ABI-009 and nivolumab on overall survival in advanced soft tissue sarcoma


Other Outcome Measures:
  1. Disease control rate and PD-L1 expression in tumors [ Time Frame: 30 months ]
    Correlation between disease control rate and PD-L1 expression in patients' tumors



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

A patient will be eligible for inclusion in this study only if all of the following criteria are met:

  1. Patients must have a histologically confirmed diagnosis of UPS, LPS, CS, OS or Ewing sarcoma that is either metastatic or locally advanced and for which surgery is not a recommended option.
  2. Patients must have one or more measurable target lesions by CT scan or MRI. Measurable disease by RECIST v1.1.
  3. Patients must not have been previously treated with a PD-1 inhibitor in combination with an mTOR inhibitor.
  4. 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.
  5. Eligible patients, 18 years or older, with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  6. Patients must have the following blood chemistry levels at screening (obtained ≤14 days prior to enrollment (local laboratory):

    1. total bilirubin ≤1.5 x upper limit of normal (ULN) mg/dl
    2. AST ≤2.5 x ULN (≤5 x ULN if attributable to liver metastases)
    3. serum creatinine ≤1.5 x ULN
  7. Adequate biological parameters as demonstrated by the following blood counts at screening (obtained ≤14 days prior to enrollment, local laboratory):

    1. Absolute neutrophil count (ANC) ≥1.5 × 109/L;
    2. Platelet count ≥100,000/mm3 (100 × 109/L);
    3. Hemoglobin ≥9 g/dL.
  8. Serum triglyceride <300 mg/dL; serum cholesterol < 350 mg/dL.
  9. 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.

  10. Life expectancy of >3 months, as determined by the investigator.
  11. Ability to understand and sign informed consent.
  12. 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:

  1. Concurrent or prior immunotherapy with a PD-1 inhibitor in combination with an mTOr inhibitor.
  2. 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.
  3. Active gastrointestinal bleeding.
  4. Pre-existing thyroid abnormality is allowed provided thyroid function can be controlled with medication.
  5. 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).
  6. 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.
  7. 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).
  8. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy.
  9. Unstable coronary artery disease or myocardial infarction during preceding 6 months.
  10. Receiving any concomitant antitumor therapy.
  11. Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension.
  12. 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.
  13. Known Human Immunodeficiency Virus (HIV).
  14. Active Hepatitis B or Hepatitis C.
  15. Non-oncology vaccine therapy used for prevention of infectious disease within 4 weeks of trial enrollment
  16. 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)
  17. Systemic immunosuppression, including HIV positive status with or without AIDS
  18. Skin rash (psoriasis, eczema) affecting > 25% body surface area
  19. Inflammatory bowel disease (Crohn's or ulcerative colitis)
  20. Ongoing or uncontrolled diarrhea within 4 weeks of trial enrollment
  21. Recent history of acute diverticulitis, intraabdominal abscess or gastrointestinal obstruction within 6 months of trial enrollment, which are known risk factors for bowel perforation
  22. Current, active or previous history of heavy alcohol abuse
  23. Pituitary endocrinopathy
  24. Adrenal insufficiency or excess

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03190174


Contacts
Contact: Erlinda M Gordon, MD 310-552-9999 egordon@sarcomaoncology.com
Contact: Victoria Chua-Alcala 310-552-9999 vchua@sarcomaoncology.com

Locations
United States, California
Sarcoma Oncology Research Center Recruiting
Santa Monica, California, United States, 90403
Contact: Erlinda M Gordon, MD    310-552-9999    egordon@sarcomaoncology.com   
Contact: Victoria Chua-Alcala    310-552-9999    vchua@sarcomaoncology.com   
Principal Investigator: Erlinda M Gordon, MD         
Sub-Investigator: Sant P Chawla, MD         
Sub-Investigator: Kamalesh K Sankhala, MD         
Sub-Investigator: Doris Quon, MD         
Sponsors and Collaborators
Sarcoma Oncology Research Center, LLC
Aadi, LLC
Investigators
Principal Investigator: Erlinda M Gordon, MD Sarcoma Oncology Research Center

Publications of Results:
Responsible Party: Sarcoma Oncology Research Center, LLC
ClinicalTrials.gov Identifier: NCT03190174     History of Changes
Other Study ID Numbers: SOC-1701
First Posted: June 16, 2017    Key Record Dates
Last Update Posted: September 6, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Osteosarcoma
Sarcoma
Sarcoma, Ewing
Liposarcoma
Chondrosarcoma
Histiocytoma, Malignant Fibrous
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Adipose Tissue
Histiocytoma
Neoplasms, Fibrous Tissue
Nivolumab
Sirolimus
Everolimus
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Immunosuppressive Agents