Nab-Sirolimus and Pazopanib Hydrochloride in Treating Patients With Advanced Nonadipocytic Soft Tissue Sarcomas

A Phase 1/2 Study of Nab-Sirolimus With Pazopanib (VOTRIENT®) in Patients With Advanced Nonadipocytic Soft-Tissue Sarcomas

This phase I/II trial studies the side effects and best dose of nab-sirolimus and how well it works when given together with pazopanib hydrochloride in treating participants with nonadipocytic soft tissue sarcomas that has spread to other places in the body (advanced). Nab-sirolimus and pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Study Overview

• Status: Active, not recruiting
• Conditions: Advanced Soft Tissue Sarcoma; Metastatic Soft Tissue Sarcoma; Locally Advanced Soft Tissue Sarcoma
• Intervention / Treatment: Drug: Sirolimus Albumin-bound Nanoparticles; Drug: Pazopanib hydrochloride

Detailed Description

OUTLINE: This is a phase I, dose-escalation study of nanoparticle albumin-bound rapamycin followed by a phase II study.

Participants receive nab-sirolimus intravenously (IV) on days 1 and 8 or day 1 only and pazopanib hydrochloride orally (PO) daily on days 1-21. Cycles repeat every 21 days until unequivocal clinical disease progression, unacceptable toxicity, or until in the opinion of the investigator the patient is no longer benefiting from therapy, or at the patient's discretion.

After completion of study treatment, participants are followed up at 30 days, then every 12 weeks.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subjects, >= 18 years old, must have a histologically confirmed diagnosis of non-adipocytic soft tissue sarcoma (STS) that is either metastatic or locally advanced and for which curative therapy is not available, surgery is not a recommended option, and pazopanib treatment is indicated.
• Subjects must have one or more measurable target lesions by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1, assessed via computed tomography (CT) scan or magnetic resonance imaging (MRI).
• Clinical or radiological progression or failure due to toxicity on at least 1 prior regimen of systemic treatment for advanced disease. Subjects may not have received more than 4 prior lines of systemic therapy (no more than 2 prior therapies may be combination cytotoxic therapies). Neo-adjuvant/adjuvant/maintenance treatments are not included for this criterion.

• Last dose of prior therapy must have been completed a minimum of 14 days prior to start of protocol therapy. All ongoing toxicities related to prior therapy must be resolved or grade 1 (except alopecia).

  * NOTE: Toxicities from prior therapy that have resolved with sequelae (e.g. hypothyroidism) and are asymptomatic or well-controlled are not exclusionary.

• Total bilirubin =< upper limit of normal (ULN) mg/dL (Subjects with known Gilbert's syndrome and a total bilirubin =< 3 mg/dl are permitted to enroll to phase 2/expansion phase only with sponsor-investigator approval).
• Aspartate aminotransferase (AST) =< 2.5 x ULN and alanine aminotransferase (ALT) =< 2.5 x ULN.
• Serum creatinine =<1.5 x ULN (If serum creatinine is > 1.5 mg/dL, calculated creatinine clearance > 50 mL/min using the Cockcroft-Gault formula may be included).
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L.
• Platelet count >= 100,000/mm^3 (100 x 10^9/L).
• Hemoglobin >= 9 g/dL.
• Serum triglyceride =< 300 mg/dL.
• Serum cholesterol =< 350 mg/dL.
• Baseline cardiac left ventricular ejection fraction (LVEF) within institutional limits of normal (by echocardiogram or multigated acquisition [MUGA] study).
• Baseline electrocardiogram with corrected QT (QTc) < 480 millisecond (Bazett's).
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

• Male or non-pregnant and non-breast feeding female:

  • Females of child-bearing potential must agree to use highly effective contraception without interruption from initiation of therapy and while on study medication and have a negative serum pregnancy test (beta human chorionic gonadotropin [beta-hCG]) result at screening and agree to ongoing pregnancy testing during the course of the study, and at the end of study treatment. A highly effective method of contraception is defined as one that results in a low failure rate (that is, < 1% per year), when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine contraceptive devices, sexual abstinence, or a vasectomized partner.
  • 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.
• 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:

• Soft tissue sarcomas with biology or defined treatments for which pazopanib is not indicated, including adipocytic STS, gastrointestinal stromal tumors (GIST), or Kaposi's sarcoma.
• Previously received an mTOR (mammalian target of rapamycin) inhibitor or angiogenesis inhibitor.
• Known active uncontrolled or symptomatic central nervous system (CNS) metastases. A subject 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.
• Subjects with hemoptysis, central nervous system hemorrhage or gastrointestinal hemorrhage within the last 6 months prior to treatment are excluded due to pazopanib-associated risk of bleeding.
• Subjects with severe hepatic impairment and active gastrointestinal bleeding.
• Uncontrolled serious medical or psychiatric illness.
• Subjects with a currently active second malignancy other than non-melanoma skin cancers, carcinoma in situ of the cervix, resected incidental prostate cancer, or other adequately treated carcinoma-in-situ are ineligible. Subjects are not considered to have a currently active malignancy if they have completed therapy and are free of disease for >= 1 year).
• 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).
• No clinically significant gastrointestinal abnormalities including malabsorption syndrome, major resection of the stomach or small bowel that could affect the absorption of study drug, active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation, history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment.
• Uncontrolled diabetes mellitus as defined by hemoglobin A1C (HbA1c) > 8% despite adequate therapy.
• Subjects with unstable coronary artery disease, myocardial infarction, or an arterial thromboembolic event during preceding 6 months.
• Subjects 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 nab-sirolimus. Additionally, use of any known CYP3A4 substrates with narrow therapeutic window (such as fentanyl, alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, terfenadine) within the 14 days prior to receiving the first dose of nab-sirolimus.
• Active hepatitis B or hepatitis C infection.
• Systemic immunosuppression, including human immunodeficiency virus (HIV) positive status with or without acquired immunodeficiency syndrome (AIDS).
• Subjects with history of intestinal perforations, fistula, hemorrhages and/or hemoptysis =< 6 months prior to first study treatment.
• Subjects with hypercholesterolemia receiving ongoing treatment with simvastatin.
• Subjects who have had major surgery within 28 days of planned initiation of protocol therapy, or patients who have/have had wound dehiscence, or other open wounds (including diabetic or infectious wounds) with active wound complications.
• Subjects with prior history of severe hypersensitivity (grade 3 or higher) to any known drug excipients, including anaphylaxis to human serum albumin.
• Subjects with uncontrolled hypertension, defined as an average systolic blood pressure (SBP) >= 140 mmHg or an average diastolic blood pressure (DBP) >= 90 mmHg despite best supportive care measures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (ABI-009, pazopanib); Participants receive nab-sirolimus intravenously (IV) on days 1 and 8 or day 1 only and pazopanib hydrochloride orally (PO) daily on days 1-21. Cycles repeat every 21 days until unequivocal clinical disease progression, unacceptable toxicity, or until in the opinion of the investigator the patient is no longer benefiting from therapy, or at the patient's discretion.

Drug: Sirolimus Albumin-bound Nanoparticles; Given IV; Other Names: ABI-009; Fyarro; Nab-Rapamycin; Nanoparticle Albumin-Bound Rapamycin; Nanoparticle Albumin-bound Sirolimus; Sirolimus Protein-bound Particles; Drug: Pazopanib hydrochloride; Given PO; Other Names: Votrient

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Maximum-tolerated Dose (MTD) of Nab-rapamycin in Combination With Pazopanib (Phase I) - Nab-Rapamycin Dose	Will be estimated using dose-limiting toxicities (DLTs). Will use a Simon's minimax design.	First 2 cycles (3-week cycles, 21 days each)
The Maximum-tolerated Dose (MTD) of Nab-rapamycin in Combination With Pazopanib (Phase I) - Pazopanib Dose	Will be estimated using dose-limiting toxicities (DLTs). Will use a Simon's minimax design.	First 2 cycles (3-week cycles, 21 days each)
Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)	A DLT is defined as any Grade 3 or greater adverse event (AE), at least possibly related to either or both nab-sirolimus and pazopanib. Only toxicities with a clearly identified and documented alternative explanation may be deemed non-DLT. Dose-limiting toxicities include any death not clearly due to underlying disease or extraneous causes, or persistent intolerable nonhematologic AE of any grade that requires dose reduction or permanent discontinuation of the study drug, in the opinion of the investigator.	First 2 cycles (3-week cycles, 21 days each)
Dose Limiting Toxicities	A Dose-limiting toxicity is defined as any Grade 3 or greater adverse event (AE), at least possibly related to either or both nab-Sirolimus or pazopanib. Only toxicities with clearly identified and documented alternative explanation may be deemed non-DLT. Dose-limiting toxicities include any death not clearly due to underlying disease or extraneous causes, or persistent intolerable nonhematologic Ae of any grade that requires dose reduction or permanent discontinuation of the study drug, in the opinion of the investigator.	First 2 cycles (3 week cycles, 21 days each)
Progression-free Survival (PFS) Rate (Phase II)	Will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 where progression is defined as a 20% increase in the sum of the longest diameter of target lesions where the sum must also demonstrate an absolute increase of at least 5 mm, or the appearance of new lesions. Will be assessed via descriptive statistics.	At 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events Profile (Phase I and II)	Will be based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0	Up to 30 days after last dose
Median PFS (Phase II)	Will be assessed using RECIST v1.1. Will be assessed via descriptive statistics.	At 6 months
Progression-Free Survival Rate (Phase II)	Will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Will be assessed via descriptive statistics.	At 6 months
Median Overall Survival (OS) (Phase II)	Will be summarized using descriptive statistics.	At 12 months
Overall Survival (Phase II)	Will be assessed using descriptive statistics.	12 months
Objective Response Rate (CR + PR) (Phase II)	Will be based on RECIST v1.1. Will be evaluated by CT imaging.	Up to 2 years
Disease Control Rate (Complete Response [CR] + Partial Response [PR] + Stable Disease [SD]) (Phase II)	Will be based on RECIST v1.1evaluated by computed tomography (CT) imaging. Per RECIST V1.1, Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >= 30% decrease in the sum of diameters of target lesions; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD).	at 24 weeks
Duration of Response (Phase II)	Will be evaluated by CT imaging.	Up to 2 years

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: Aadi Bioscience, Inc.
• Investigators: Principal Investigator: Lee Cranmer, MD, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2019
• Primary Completion (Actual): November 17, 2022
• Study Completion (Estimated): February 28, 2025

Study Registration Dates

• First Submitted: September 4, 2018
• First Submitted That Met QC Criteria: September 4, 2018
• First Posted (Actual): September 7, 2018

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 11, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus; Temsirolimus; MTOR Inhibitors
• Other Study ID Numbers: RG1718053; 10015 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); NCI-2018-01624 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No