Clinical Trials /

TAK-659 and Paclitaxel in Treating Patients With Advanced Solid Tumors

NCT03756818

Description:

This phase I trial studies the best dose and side effects of TAK-659 and paclitaxel in treating patients with advanced solid tumors. TAK-659 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel, 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 TAK-659 and paclitaxel may work better in treating patients with advanced solid tumors.

Related Conditions:
  • Malignant Ovarian Epithelial Tumor
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: TAK-659 and Paclitaxel in Treating Patients With Advanced Solid Tumors
  • Official Title: A Phase I Study of TAK-659 and Paclitaxel in Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: 2017-0422
  • SECONDARY ID: NCI-2018-02665
  • SECONDARY ID: 2017-0422
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03756818

Conditions

  • Advanced Malignant Solid Neoplasm
  • KRAS Gene Mutation
  • Ovarian Carcinoma
  • Refractory Malignant Solid Neoplasm
  • Refractory Ovarian Carcinoma

Interventions

DrugSynonymsArms
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratTreatment (TAK-659 and paclitaxel)
Spleen Tyrosine Kinase Inhibitor TAK-659Spleen Tyrosine Kinase Inhibitor TAK659, syk Inhibitor TAK-659, syk Inhibitor TAK659, syk-Inhibitor TAK-659, syk-Inhibitor TAK659, TAK-659, TAK659Treatment (TAK-659 and paclitaxel)

Purpose

This phase I trial studies the best dose and side effects of TAK-659 and paclitaxel in treating patients with advanced solid tumors. TAK-659 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel, 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 TAK-659 and paclitaxel may work better in treating patients with advanced solid tumors.

Detailed Description

      PRIMARY OBJECTIVES I. To define the maximum tolerated doses (MTD) of spleen tyrosine kinase
      inhibitor TAK-659 (TAK-659) and paclitaxel.

      II. To define the safety profiles of the combination.

      SECONDARY OBJECTIVES I. To evaluate clinical response signals to the combination. II. To
      analyze pharmacokinetic interactions between TAK-659 and paclitaxel. III. To assess
      predictive biomarkers (baseline molecular mutation status) and/or resistant pathways by
      comparing molecular signatures at baseline versus at time of relapse in patients who have
      achieved objective responses.

      OUTLINE: This is a dose-escalation study of spleen tyrosine kinase inhibitor TAK-659 and
      paclitaxel.

      Patients receive spleen tyrosine kinase inhibitor TAK-659 orally (PO) once daily (QD) and
      paclitaxel intravenously (IV) over approximately 1 hour on days 1, 8, and 15. Courses repeat
      every 28 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 28 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (TAK-659 and paclitaxel)ExperimentalPatients receive spleen tyrosine kinase inhibitor TAK-659 PO QD and paclitaxel IV over approximately 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Paclitaxel
  • Spleen Tyrosine Kinase Inhibitor TAK-659

Eligibility Criteria

        Inclusion Criteria:

          -  All patients have advanced malignancy (high-grade epithelial ovarian cancer or cancer
             harboring K-RAS mutation), either refractory to standard therapy or for which no
             effective standard therapy is available

          -  Patients must have measurable or evaluable disease, as defined by Response Evaluation
             Criteria in Solid Tumors (RECIST) 1.1

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 and life
             expectancy of greater than 3 months and/or other performance status of 0 to 1

          -  Female patients who:

               -  Are postmenopausal for at least 1 year before the screening visit, OR

               -  Are surgically sterile, OR

               -  If they are of childbearing potential, agree to practice 1 highly effective
                  method of contraception and one additional effective (barrier) method at the same
                  time, from the time of signing the informed consent through 180 days after the
                  last dose of study drug, OR

               -  Agree to practice true abstinence, when is in line with the preferred and usual
                  lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation,
                  symptothermal, postovulation methods), withdrawal, spermicides only, and
                  lactational amenorrhea are not acceptable methods of contraception. Female and
                  male condoms should not be used together)

               -  Agree not to donate eggs (ova) during the course of this study or 180 days after
                  receiving their last dose of study drug

          -  Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:

               -  Agree to practice effective barrier contraception during the entire study
                  treatment period and through 180 days after the last dose of study drug, or

               -  Agree to practice true abstinence, when this is in line with the preferred and
                  usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation,
                  symptothermal, postovulation methods for the female partner] and withdrawal are
                  not acceptable methods of contraception. Female and male condoms should not be
                  used together.)

               -  Agree not to donate sperm during the course of this study or within 180 days
                  after receiving their last dose of study drug

          -  Absolute neutrophil count (ANC) >= 1,500/uL

          -  Platelet count >= 100,000/uL (red blood cell count [RBC] and platelet transfusion
             allowed >= 14 days before assessment)

          -  Hemoglobin >= 8 g/dL (RBC and platelet transfusion allowed >= 14 days before
             assessment)

          -  Total bilirubin =< 1.5 x the upper limit of the normal range (ULN) (except patients
             with Gilbert's syndrome, who must have a total bilirubin =< 3.0 mg/dL)

          -  Aminotransferases alanine (ALT) and aspartate (AST) =< 2.5 x ULN or =< 5 x ULN if
             hepatic metastasis

          -  Serum creatinine =< 1 x ULN and creatine clearance >= 60 mL/min either as estimated by
             the Cockcroft-Gault equation or based on urine collection (12 or 24 hours) if serum
             creatinine is abnormal

          -  Lipase =< 1.5 x ULN with no clinical symptoms suggestive of pancreatitis or
             cholecystitis

          -  Amylase =< 1.5 x ULN with no clinical symptoms suggestive of pancreatitis or
             cholecystitis

          -  Blood pressure =< grade 1 (hypertensive patients are permitted if their blood pressure
             is controlled to =< grade 1 by hypertensive medications and glycosylated hemoglobin is
             =< 6.5%)

          -  Recovered (=< grade 1 toxicity) from the reversible effects of prior anticancer
             therapy

          -  Voluntary written consent must be given before performance of any study related
             procedure not part of standard medical care, with the understanding that consent may
             be withdrawn by the patient at any time without prejudice to future medical care

          -  Patients may receive palliative radiation therapy immediately before or during the
             treatment if the radiation therapy is not delivered to the sole target lesions

          -  Patients must be able to take oral medications without medical history of
             malabsorption or other chronic gastrointestinal disease, or conditions that may hamper
             compliance and/or absorption of the study agents

          -  Patients have prior therapy with a taxane

          -  Patients agree to provide archival tissue block or 10 formalin-fixed paraffin-embedded
             (FFPE) slides paraffin for use in pharmacodynamics correlative studies

        Exclusion Criteria:

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection requiring intravenous antibiotics, symptomatic congestive heart failure (New
             York Heart Association [NYHA] Class III or IV), or history of myocardial infarction,
             unstable angina, stroke or transient ischemic attack within 6 months prior to study
             enrollment

          -  Active brain metastases or leptomeningeal metastases

          -  Known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to any
             particular combination drug will result in a patient being ineligible for inclusion in
             that particular cohort

          -  History of drug-induced pneumonitis requiring treatment with steroids; history of
             idiopathic pulmonary fibrosis, organizing pneumonia, or evidence of active pneumonitis
             on screening chest computed tomography (CT) scan; history of radiation pneumonitis in
             the radiation field (fibrosis) is permitted

          -  Female patients who are both lactating and breastfeeding or have a positive serum
             pregnancy test during the screening period or a positive urine pregnancy test on day 1
             before first dose of study drug

          -  Any serious medical or psychiatric illness that could, in the investigator's opinion,
             potentially interfere with the completion of treatment according to this protocol

          -  Life-threatening illness unrelated to cancer that could, in the investigator's
             opinion, make the patient not appropriate for this study

          -  Known human immunodeficiency virus (HIV) positive

          -  Known hepatitis B surface antigen positive, or known or suspected active hepatitis C
             infection

          -  Any treatment specific for systemic tumor control within 3 weeks prior to the
             initiation of the study drugs; or within 2 weeks if cytotoxic agents were given weekly
             (within 6 weeks for nitrosoureas or mitomycin C), or within 5 half-lives for targeted
             agents with half-lives and pharmacodynamic effects lasting less than 4 days (that
             includes but is not limited to erlotinib, sorafenib, sunitinib, bortezomib, and other
             similar agents), or failure to recover from toxic effects of any therapy prior to the
             study drug treatment

          -  Any clinically significant comorbidities, such as uncontrolled pulmonary disease,
             known impaired cardiac function or clinically significant cardiac disease (specified
             below), active central nervous system (CNS) disease, active infection, or any other
             condition that could compromise the patient's participation in the study. Patients
             with any of the following cardiovascular conditions are excluded:

               -  Acute myocardial infarction within 6 months before starting study drug

               -  Current or history of New York Heart Association Class III or IV heart failure

               -  Evidence of current, uncontrolled cardiovascular conditions including cardiac
                  arrhythmias, angina, pulmonary hypertension, or electrocardiographic evidence of
                  acute ischemia or active conduction system abnormalities

               -  Fridericia corrected QT interval (QTcF) > 450 milliseconds (msec) (men) or > 475
                  msec (women) on a 12-lead electrocardiogram (ECG) during the screening period

               -  Abnormalities on 12-lead ECG including, but not limited to, changes in rhythm and
                  intervals that, in the opinion of the investigator, are considered to be
                  clinically significant

          -  Use or consumption of any of the following substances:

               -  Medications or supplements that are known to be inhibitors of P-glycoprotein (gp)
                  and/or strong reversible inhibitors of CYP3A within 5 times the inhibitor
                  half-life (if a reasonable half-life estimate is known), or within 7 days (if a
                  reasonable half-life estimate is unknown), before the first dose of study drug.
                  In general, the use of these agents is not permitted during the study except in
                  cases where an adverse event (AE) must be managed

               -  Medications or supplements that are known to be strong CYP3A mechanism-based
                  inhibitors or strong CYP3A inducers and/or P-gp inducers within 7 days, or within
                  5 times the inhibitor or inducer half-life (whichever is longer), before the
                  first dose of study drug. In general, the use of these agents is not permitted
                  during the study except in cases where an AE must be managed

               -  Grapefruit-containing food or beverages within 5 days before the first dose of
                  study drug. Note that grapefruit-containing food and beverages are not permitted
                  during the study

          -  Major surgery within 14 days before the first dose of study drug and not recovered
             fully from any complications from surgery

          -  Systemic infection requiring parenteral antibiotic therapy or other serious infection
             (bacterial, fungal or viral) within 21 days before the first dose of study drug.
             Patients who are at substantial risk of developing an infection may receive
             prophylaxis at the study of study treatment per investigator's discretion

          -  Active secondary malignancy that requires treatment. Patients with non-melanoma skin
             cancer or carcinoma in situ of any type are not excluded if they have undergone
             complete resection and are considered disease-free at the time of study entry

          -  Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
             absorption or tolerance of TAK-659 including difficulty swallowing tablets or diarrhea
             > grade 1 despite supportive therapy. History of abdominal fistula, gastrointestinal
             perforation, or intra-abdominal abscess within 6 months prior to study enrollment

          -  Patients with clinical bleeding, active gastric or duodenal ulcer

          -  Grade 2 or higher peripheral neuropathy

          -  Left ventricular ejection fraction (LVEF) is less than 50% on echocardiography (ECHO)
             or multiple-gated acquisition (MUGA) scanning or QTc is greater than 450 milliseconds
             (msec) for men and greater than 475 msec for women at screening

          -  Treatment with high-dose corticosteroids for anticancer purposes within 14 days before
             the first dose of TAK-659; daily dose equivalent to 10 mg oral prednisone or less is
             permitted. Corticosteroids for topical use or in nasal spray or inhalers, or for
             premedication for paclitaxel are allowed

          -  Lack of suitable venous access for the study-required blood sampling

          -  Grade 1 or higher ophthalmologic disease
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events and serious adverse events assessed by NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 5.0
Time Frame:Up to 4 years
Safety Issue:
Description:Adverse events (clinical manifestations and laboratory tests) and serious adverse events will be assessed by clinical symptoms and laboratory values, evaluation of vital signs, and performance of physical exam with a special attention to treatment-related fatigue, gastrointestinal symptoms, cardiovascular events, myelosuppression, and neurotoxicity.

Secondary Outcome Measures

Measure:Dose-limiting toxicity
Time Frame:Up to 28 days
Safety Issue:
Description:
Measure:Categorization of response based on Response Evaluation Criteria in Solid Tumors 1.1
Time Frame:Up to 4 years
Safety Issue:
Description:A patient will be determined as having a response if he/she has complete response, partial response or stable disease for at least 4 months; a patient will be determined as a non-response if there is no evidence of response by 4 months during this study.
Measure:Minimum detectable effect size
Time Frame:Baseline up to 28 days post-treatment
Safety Issue:
Description:Will use the Wilcoxon signed-rank test to calculate the minimum detectable effect size on biomarker data and tumor response. A mixed model accounting for patient effects will be used to analyze longitudinal data (including biomarker data) over time.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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