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Pembrolizumab and Doxorubicin Hydrochloride in Treating Patients With Sarcoma That is Metastatic or Cannot Be Removed by Surgery

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ClinicalTrials.gov Identifier: NCT02888665
Recruitment Status : Completed
First Posted : September 5, 2016
Results First Posted : May 26, 2021
Last Update Posted : May 26, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Seth Pollack, Northwestern University

Tracking Information
First Submitted Date  ICMJE August 30, 2016
First Posted Date  ICMJE September 5, 2016
Results First Submitted Date  ICMJE March 12, 2021
Results First Posted Date  ICMJE May 26, 2021
Last Update Posted Date May 26, 2021
Actual Study Start Date  ICMJE December 5, 2016
Actual Primary Completion Date March 17, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 3, 2021)
  • Maximum Tolerated Dose (MTD) of Doxorubicin Hydrochloride Plus Pembrolizumab According to the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 4.0 (Phase I) [ Time Frame: Up to 42 days (6 weeks) ]
    Defined as a dose limiting toxicity (DLT) in less than 2 of 6 subjects. Only Phase 1 subjects will be evaluated for MTD.
  • Objective Response Rate (ORR) (Phase II) [ Time Frame: Up to 2 years ]
    Evaluated per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT. Complete Response (CR) is a complete elimination of the tumor; Partial Response (PR) is 30% reduction. If a subject experienced a PR, this was required to be confirmed with a second scan at the next appropriate cycle.
Original Primary Outcome Measures  ICMJE
 (submitted: August 30, 2016)
  • Maximum tolerated dose of doxorubicin hydrochloride together with pembrolizumab according to the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) version 4.0 (Phase I) [ Time Frame: Up to 42 days (6 weeks) ]
    Defined as a dose limiting toxicity in less than 2 of 6 patients.
  • Objective Response Rate (ORR) (Phase II) [ Time Frame: Up to 2 years ]
    Will compare ORR with historical rates.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 3, 2021)
  • Duration of Response [ Time Frame: Up to 2 years ]
    Duration of response is the mean time to progression for all subjects who responded.
  • Median Progression-free Survival (PFS) [ Time Frame: Up to 2 years ]
    The Kaplan-Meier method will be used to estimate median PFS.
  • Overall Survival (OS) [ Time Frame: Up to 2 years ]
    The Kaplan-Meier method will be used to estimate median OS.
  • Time to Response [ Time Frame: Up to 2 years ]
    Average time to response
Original Secondary Outcome Measures  ICMJE
 (submitted: August 30, 2016)
  • Duration of Response [ Time Frame: Up to 2 years ]
  • Incidence of adverse events, according to NCI CTCAE version 4.0 [ Time Frame: Up to 2 years ]
  • Median Progression-free Survival (PFS) [ Time Frame: Up to 2 years ]
    The Kaplan-Meier method will be used to estimate median PFS.
  • Overall Survival (OS) [ Time Frame: Up to 2 years ]
    The Kaplan-Meier method will be used to estimate median OS.
  • Time to Response [ Time Frame: Up to 2 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: August 30, 2016)
Change in biomarkers [ Time Frame: Baseline to 2 years ]
Summary statistics will be used to for describing changes across time. In addition, the time course of biomarker outcomes will be investigated graphically by summary plots or individual patient plots. Categorical data analysis and logistic regression will be used to evaluate the associations between correlative measures and clinical outcome (e.g., response, clinical benefit, time to progression, progression-free survival, and survival). Methods such as linear mixed models may be used to characterize the pattern of change over time. Kaplan-Meier methodology and Cox proportional hazards models will be used to evaluate time to event endpoints.
 
Descriptive Information
Brief Title  ICMJE Pembrolizumab and Doxorubicin Hydrochloride in Treating Patients With Sarcoma That is Metastatic or Cannot Be Removed by Surgery
Official Title  ICMJE A Trial of Pembrolizumab in Combination With Doxorubicin as Treatment for Patients With Advanced Sarcomas
Brief Summary This phase I/II trial studies the side effects and best dose of doxorubicin hydrochloride when given together with pembrolizumab and to see how well they work in treating patients with sarcoma that have spread to other parts of the body or that cannot be removed by surgery. Drugs used in chemotherapy, such as doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving doxorubicin hydrochloride together with pembrolizumab may work better in treating patients with sarcoma.
Detailed Description

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of the combination of pembrolizumab and doxorubicin hydrochloride (doxorubicin) in patients with advanced soft tissue sarcoma (STS).

II. To assess the clinical response rate of advanced soft tissue sarcoma (STS) patients receiving the combination of pembrolizumab and doxorubicin.

SECONDARY OBJECTIVES:

I. To explore the clinical activity of pembrolizumab in subjects with advanced STS with respect to time to response.

II. To explore the clinical activity of pembrolizumab in subjects with advanced STS with respect to duration of response.

III. To explore the clinical activity of pembrolizumab in subjects with advanced STS with respect to progression-free survival (PFS).

IV. To explore the clinical activity of pembrolizumab in subjects with advanced STS with respect to overall survival.

TERTIARY OBJECTIVES:

I. To compare response rates between patients with high levels of PD-L1 expression with those who have PD-L1 absent.

OUTLINE: This is a phase I, dose-escalation study of doxorubicin hydrochloride followed by a phase II study.

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and doxorubicin hydrochloride IV over 1-3 hours on day 1 of courses 2-7 only. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Sarcoma
Intervention  ICMJE
  • Drug: Doxorubicin Hydrochloride
    Given IV
    Other Names:
    • 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
    • ADM
    • Adriacin
    • Adriamycin
    • Adriamycin Hydrochloride
    • Adriamycin PFS
    • Adriamycin RDF
    • ADRIAMYCIN, HYDROCHLORIDE
    • Adriamycine
    • Adriblastina
    • Adriblastine
    • Adrimedac
    • Chloridrato de Doxorrubicina
    • DOX
    • DOXO-CELL
    • Doxolem
    • Doxorubicin.HCl
    • Doxorubin
    • Farmiblastina
    • FI 106
    • FI-106
    • hydroxydaunorubicin
    • Rubex
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Biological: Pembrolizumab
    Given IV
    Other Names:
    • Keytruda
    • Lambrolizumab
    • MK-3475
    • SCH 900475
Study Arms  ICMJE Experimental: Treatment (pembrolizumab, doxorubicin hydrochloride)
Patients receive pembrolizumab IV over 30 minutes on day 1 and doxorubicin hydrochloride IV over 1-3 hours on day 1 of courses 2-7 only. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: Doxorubicin Hydrochloride
  • Other: Laboratory Biomarker Analysis
  • Biological: Pembrolizumab
Publications * Pollack SM, Redman MW, Baker KK, Wagner MJ, Schroeder BA, Loggers ET, Trieselmann K, Copeland VC, Zhang S, Black G, McDonnell S, Gregory J, Johnson R, Moore R, Jones RL, Cranmer LD. Assessment of Doxorubicin and Pembrolizumab in Patients With Advanced Anthracycline-Naive Sarcoma: A Phase 1/2 Nonrandomized Clinical Trial. JAMA Oncol. 2020 Nov 1;6(11):1778-1782. doi: 10.1001/jamaoncol.2020.3689.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 29, 2019)
37
Original Estimated Enrollment  ICMJE
 (submitted: August 30, 2016)
47
Actual Study Completion Date  ICMJE October 9, 2020
Actual Primary Completion Date March 17, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Be willing and able to provide written informed consent/assent for the trial
  • Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Have metastatic or unresectable sarcoma
  • Have a performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  • Absolute neutrophil count (ANC) >= 1,500/mcL (within 10 days of treatment initiation)
  • Platelets >= 100,000/mcL (within 10 days of treatment initiation)
  • Hemoglobin >= 9 g/dL (within 10 days of treatment initiation) or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
  • Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (within 10 days of treatment initiation)
  • Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 10 days of treatment initiation)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (within 10 days of treatment initiation)
  • Albumin >= 2.5 mg/dL (within 10 days of treatment initiation)
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
  • Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
  • Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
  • Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
  • Ejection fraction > 45% by either multi-gated acquisition scan (MUGA) scan or echocardiogram

Exclusion Criteria:

  • Has prior treatment using an anthracycline
  • Has one of the following sarcoma subtypes where combining anthracyclines with other chemotherapies is established as the standard of care: osteosarcoma, Ewings sarcoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma
  • Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
  • Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
  • Has a known history of active TB (bacillus tuberculosis)
  • Hypersensitivity to pembrolizumab or any of its excipients
  • Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
  • Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent

    • Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study
    • Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
  • Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
  • Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • Has known history of, or any evidence of active, non-infectious pneumonitis
  • Has an active infection requiring systemic therapy
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
  • Has received prior therapy with an anti-programed death receptor 1 (PD-1), anti-PD-L1, anti-program death receptor ligand 2 (PD-L2) agent or anti-CTLA4
  • Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
  • Has received a live vaccine within 30 days of planned start of study therapy

    • Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02888665
Other Study ID Numbers  ICMJE 9624
NCI-2016-01286 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9624 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
RG9216017 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Seth Pollack, Northwestern University
Study Sponsor  ICMJE Fred Hutchinson Cancer Research Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Seth Pollack Fred Hutch/University of Washington Cancer Consortium
PRS Account Fred Hutchinson Cancer Research Center
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP