Clinical Trials /

Ribociclib and Doxorubicin in Treating Patients With Metastatic or Advanced Soft Tissue Sarcomas That Cannot Be Removed by Surgery

NCT03009201

Description:

This phase Ib trial studies the side effects and best dose of the CDK4/6 inhibitor ribociclib when given together with doxorubicin in treating patients with soft tissue sarcomas that has spread to other places or that cannot be removed by surgery. Ribociclib may stop the growth of sarcoma tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as doxorubicin, 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. Giving ribociclib for a week prior to standard treatment with doxorubicin may work better in treating patients with soft tissue sarcoma.

Related Conditions:
  • Angiosarcoma
  • Epithelioid Sarcoma
  • Fibrosarcoma
  • Leiomyosarcoma
  • Liposarcoma
  • Malignant Peripheral Nerve Sheath Tumor
  • Myxofibrosarcoma
  • Pleomorphic Rhabdomyosarcoma
  • Soft Tissue Sarcoma
  • Synovial Sarcoma
  • Undifferentiated Pleomorphic Sarcoma
  • Undifferentiated Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Ribociclib and Doxorubicin in Treating Patients With Metastatic or Advanced Soft Tissue Sarcomas That Cannot Be Removed by Surgery
  • Official Title: A Phase 1B Study of Ribociclib in Combination With Doxorubicin in Advanced Soft Tissue Sarcomas

Clinical Trial IDs

  • ORG STUDY ID: STUDY00016070
  • SECONDARY ID: NCI-2016-01794
  • SECONDARY ID: STUDY00016070
  • SECONDARY ID: P30CA069533
  • NCT ID: NCT03009201

Conditions

  • Metastatic Angiosarcoma
  • Metastatic Epithelioid Sarcoma
  • Metastatic Fibrosarcoma
  • Metastatic Leiomyosarcoma
  • Metastatic Liposarcoma
  • Metastatic Malignant Peripheral Nerve Sheath Tumor
  • Metastatic Synovial Sarcoma
  • Metastatic Undifferentiated Pleomorphic Sarcoma
  • Myxofibrosarcoma
  • Pleomorphic Rhabdomyosarcoma
  • Stage III Soft Tissue Sarcoma
  • Stage IV Soft Tissue Sarcoma
  • Undifferentiated (Embryonal) Sarcoma

Interventions

DrugSynonymsArms
Doxorubicin5,12-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 HYDROCHLORIDE, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, RubexTreatment (ribociclib, doxorubicin hydrochloride)
RibociclibLEE-011, LEE011Treatment (ribociclib, doxorubicin hydrochloride)

Purpose

This phase Ib trial studies the side effects and best dose of the CDK4/6 inhibitor ribociclib when given together with doxorubicin in treating patients with soft tissue sarcomas that has spread to other places or that cannot be removed by surgery. Ribociclib may stop the growth of sarcoma tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as doxorubicin, 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. Giving ribociclib for a week prior to standard treatment with doxorubicin may work better in treating patients with soft tissue sarcoma.

Detailed Description

      This is a dose-escalation study of the CDK4/6 inhibitor ribociclib in combination with
      standard-dose doxorubicin.

      PRIMARY OBJECTIVES:

      I. To determine the recommended phase 2 dose (RP2D) of ribociclib in combination with
      doxorubicin in subjects with advanced soft tissue sarcomas.

      SECONDARY OBJECTIVES:

      I. To assess preliminary anti-tumor activity of ribociclib in combination with doxorubicin in
      subjects with advanced soft tissue sarcomas (Progression-Free Survival and Overall Response
      Rate).

      II. To characterize the safety and tolerability of ribociclib in combination with
      doxorubicin.

      A mandatory biopsy will be obtained after 7 days of ribociclib treatment.

      TREATMENT: Patients receive ribociclib orally (PO) daily on days 1-7, and doxorubicin
      intravenously (IV) on day 10. Treatment repeats every 21 days for up to 6 courses in the
      absence of disease progression or unacceptable toxicity. After 6 courses, patients may
      receive maintenance treatment with ribociclib PO daily on days 1-21. Courses repeat every 28
      days in the absence of disease progression or unacceptable toxicity.

      STARTING DOSE COHORT: Ribociclib 400 mg with doxorubicin 75 mg/m2.

      FOLLOW-UP: After completion of study treatment, patients are followed up at 30 days and then
      every 12 weeks for 12 months.

      RATIONALE: Over-expression of CDK4 or loss of the CDK4 inhibitor p16 are common in sarcomas
      and result in a selective growth advantage by bypassing normal cell cycle checkpoints. Intact
      pRb is required for CDK4/6 inhibition to be effective, therefore all eligible subjects must
      have documented pRb expression by IHC on archival tissue. Synergy between CDK4 inhibition and
      chemotherapy has been documented in preclinical models when given sequentially, suggestion a
      role for cell cycle synchronization.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ribociclib, doxorubicin hydrochloride)ExperimentalPatients receive ribociclib PO daily on days 1-7, and doxorubicin hydrochloride IV on day 10. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive ribociclib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Doxorubicin
  • Ribociclib

Eligibility Criteria

        Inclusion Criteria:

          -  Pathologically confirmed diagnosis of intermediate or high-grade soft tissue sarcoma
             for which single-agent doxorubicin is appropriate therapy, including but not limited
             to:

               -  Synovial sarcoma

               -  Fibrosarcoma

               -  Undifferentiated sarcoma

               -  Liposarcoma

               -  Leiomyosarcoma

               -  Angiosarcoma

               -  Malignant peripheral nerve sheath tumor

               -  Pleomorphic rhabdomyosarcoma

               -  Myxofibrosarcoma

               -  Epithelioid sarcoma

               -  Undifferentiated pleomorphic sarcoma

          -  Locally advanced unresectable or metastatic disease with no standard curative therapy
             available

          -  Archival tumor tissue retinoblastoma-associated protein (pRb) positive by
             immunohistochemistry (IHC)

          -  Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
             criteria

          -  All races and ethnic groups will be included; for subjects between the ages of 15-18
             years only, body surface area (BSA) must be >= 1.5 m^2

          -  Ejection fraction of >= 50% by echocardiogram or multi-gated acquisition (MUGA) scan

          -  Female subjects of childbearing potential must have a negative urine beta-human
             chorionic gonadotropin (beta-hCG) pregnancy test at time of screening and within 14
             days prior to planned first dose of ribociclib

          -  Willing to use adequate contraception throughout the study and for 3 weeks after study
             drug discontinuation

          -  Meets the following standard 12-lead electrocardiography (ECG) parameters at screening
             (defined as the mean of the triplicate ECGs):

               -  Corrected QT using Fridericia's correction formula (QTcF) interval at screening <
                  450 msec for males and < 470 msec for females

               -  Resting heart rate =< 100 beats per minute (bpm)

          -  Absolute neutrophil count (ANC) >= 1.5 K/cu mm

          -  Platelets (no transfusion within prior 7 days) >= 100 K/cu mm

          -  Hemoglobin (no transfusion within prior 7 days) >= 9.0 g/dL

          -  Total bilirubin < institutional upper limit of normal (ULN), except for subjects with
             documented Gilbert's syndrome, for which =< 3.0 x ULN or direct bilirubin =< 1.5 x ULN

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT) in the
             absence of liver metastases: =< 2.5 x ULN; if the subject has liver metastases: < 5 x
             ULN

          -  Serum creatinine < 1.7 mg/dL

          -  Potassium within institutional normal limit (WNL)

          -  Corrected calcium WNL

          -  Magnesium WNL

          -  International normalized ratio (INR) =< 1.5

               -  Use of rivaroxaban, apixaban, edoxaban or warfarin is an exclusion criteria;
                  therapy with heparin, low molecular weight heparin (LMWH), dabigatran or
                  fondaparinux is allowed

          -  All prior treatment-related toxicities resolved to =< grade 1 or are determined to be
             clinically stable by the investigator

          -  Has completed prior therapies according to the criteria below:

               -  Cytotoxic chemotherapy - at least 21 days since last dose prior to first dose of
                  ribociclib

               -  Small molecule inhibitors - at least 14 days since last dose prior to first dose
                  of ribociclib

               -  Monoclonal antibodies - at least 3 half-lives since last dose prior to first dose
                  of ribociclib; exception: denosumab for bony metastases is allowable

               -  Immunotherapy (e.g. tumor vaccines) - at least 42 days since last dose prior to
                  first dose of ribociclib

               -  Radiation - at least 14 days since last dose prior to first dose of ribociclib

          -  Able to swallow capsules

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Life expectancy > 3 months

          -  Ability to understand and the willingness to sign a written informed consent document;
             subject has signed the informed consent (ICF) prior to any screening procedures being
             performed and is able to comply with protocol requirements

        Exclusion Criteria:

          -  Subjects with low grade tumors (histologic grade 1/3)

          -  Histologic diagnosis for which single-agent doxorubicin is NOT appropriate therapy,
             including but not limited to:

               -  Alveolar or embryonal rhabdomyosarcoma

               -  Ewings sarcoma or primitive neuroectodermal tumor (PNET)

               -  Osteosarcoma

               -  Gastrointestinal stromal tumor (GIST)

          -  Prior systemic therapy with an anthracycline for any indication

          -  Known hypersensitivity to any of the excipients of ribociclib or doxorubicin

          -  Currently receiving any of the following that cannot be discontinued at least 7 days
             prior to starting study drug:

               -  Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit
                  hybrids, pummelos, star-fruit, and Seville oranges

               -  Medications with a narrow therapeutic window that are predominantly metabolized
                  through CYP3A4/5

               -  Herbal supplements, such as St. John's wort; the use of marijuana or its
                  derivatives is allowed in States with statutes permitting the use of recreational
                  or medical marijuana

          -  Uncontrolled intercurrent medical condition including, but not limited to:

               -  Uncontrolled infection

               -  Symptomatic congestive heart failure (New York Heart Association [NYHA] class
                  III-IV)

               -  Acute coronary syndromes (including myocardial infarction, unstable angina,
                  coronary artery bypass grafting, coronary angioplasty, or stenting) or
                  symptomatic pericarditis within 6 months prior to screening

               -  Uncontrolled cardiac arrhythmia or arrhythmia requiring medication other than
                  beta blocker

               -  Psychiatric illness/social situations that would limit compliance with study
                  requirements

               -  Any other concurrent severe and/or uncontrolled medical condition that would, in
                  the investigator's judgment, cause unacceptable safety risks or compromise
                  compliance with the protocol (e.g. chronic pancreatitis, chronic active
                  hepatitis, etc.)

          -  Concurrent malignancy or malignancy within 3 years prior to starting study drug, with
             the exception of malignancies that have completed therapy and are considered by their
             physician to be at less than 30% risk of relapse

          -  Central nervous system (CNS) involvement unless they meet ALL of the following
             criteria:

               -  At least 4 weeks from prior therapy completion (including radiation and/or
                  surgery) to starting the study treatment

               -  Clinically stable CNS tumor at the time of screening and not receiving steroids
                  and/or enzyme-inducing anti-epileptic medications for brain metastases

          -  Impairment of gastrointestinal (GI) function or GI disease that may significantly
             alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled
             nausea/vomiting/diarrhea, malabsorption syndrome, or major small bowel resection)

          -  Known history of human immunodeficiency virus (HIV) infection (testing not mandatory);
             NOTE: HIV-positive subjects on combination antiretroviral therapy are ineligible
             because of the potential for pharmacokinetic interactions with ribociclib; in
             addition, these subjects are at increased risk of lethal infections when treated with
             marrow suppressive therapy; appropriate studies will be undertaken in subjects
             receiving combination antiretroviral therapy when indicated

          -  Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg at screening; if initial
             screening SBP is outside of the eligible range, blood pressure may be re-checked after
             intervention; SBP must be documented as stable and within the eligible range prior to
             starting study drug

          -  Currently receiving rivaroxaban, apixaban, endoxaban, warfarin or other warfarin
             derived anticoagulant; therapy with heparin, low molecular weight heparin (LMWH),
             dabigatran or fondaparinux is allowed; if transitioning from a prohibited
             anticoagulant, a minimum washout of 7 days from last dose of the prohibited medication
             is required prior to ribociclib start

          -  Participation in a prior investigational interventional study within 30 days prior to
             enrollment or within 5 half-lives of the investigational product, whichever is longer

          -  Major surgery within 14 days prior to starting study drug or has not recovered from
             surgical complications (tumor biopsy is not considered as major surgery)

          -  History of congenital long QT syndrome or torsades de pointes

          -  History of non-compliance to medical regimen or inability to grant consent

          -  Pregnant or nursing (lactating) women; breastfeeding should be discontinued
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of DLTs of adverse events graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.03
Time Frame:up to 21 days
Safety Issue:
Description:All adverse events (AEs) will be tabulated and summarized by major organ category, grade, anticipation, and drug attribution. Serious adverse events (SAE) specific incidence and exact 95% confidence interval will be provided where appropriate.

Secondary Outcome Measures

Measure:Incidence of adverse events, SAEs, assessed by NCI CTCAE v 4.03
Time Frame:Up to 12 months
Safety Issue:
Description:Analyses will be performed for all patients having received at least one dose of study drug. Serious adverse events, and AEs will be summarized using descriptive statistics.
Measure:Incidence of dose modifications (interruptions, reductions, intensity) due to adverse events
Time Frame:Up to 12 months
Safety Issue:
Description:Analyses will be performed for all patients having received at least one dose of study drug. AEs leading to withdrawal/dose interruptions/dose modification will be summarized using descriptive statistics.
Measure:Objective response rate (ORR) defined as the proportion of patients who achieved a complete response or a partial response based on RECIST v1
Time Frame:Up to 12 months
Safety Issue:
Description:The ORR, along with exact two-sided 95% confidence intervals, will be reported for the study.
Measure:Progression-free survival (PFS)
Time Frame:From first dose of protocol therapy to time of documented radiographic and/or clinical disease progression or death from any cause, whichever occurs first, assessed up to 12 months
Safety Issue:
Description:The Kaplan-Meier product limit method will be used to estimate PFS of the median PFS and PFS rates at clinically relevant time points will be provided with the 90% CI.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:OHSU Knight Cancer Institute

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