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

Sponsor

M.D. Anderson Cancer Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03756818

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

35.7

Anticipated Duration (Months)

2.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Advanced Malignant Solid Neoplasm KRAS Gene Mutation Ovarian Carcinoma Refractory Malignant Solid Neoplasm Refractory Ovarian Carcinoma	Drug: Paclitaxel Other: Pharmacokinetic Study Drug: Spleen Tyrosine Kinase Inhibitor TAK-659	Phase 1

Detailed Description

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

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

81 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Study of TAK-659 and Paclitaxel in Patients With Advanced Solid Tumors

Actual Study Start Date :

Mar 5, 2019

Anticipated Primary Completion Date :

Feb 24, 2022

Anticipated Study Completion Date :

Feb 24, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (TAK-659 and paclitaxel) Patients 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.	Drug: Paclitaxel Given IV Other Names: Anzatax Asotax Bristaxol Praxel Taxol Taxol Konzentrat Other: Pharmacokinetic Study Correlative studies Other Names: PHARMACOKINETIC PK Study Drug: Spleen Tyrosine Kinase Inhibitor TAK-659 Given PO Other Names: Spleen Tyrosine Kinase Inhibitor TAK659 syk Inhibitor TAK-659 syk Inhibitor TAK659 syk-Inhibitor TAK-659 syk-Inhibitor TAK659 TAK-659 TAK659

Arm

Intervention/Treatment

Experimental: Treatment (TAK-659 and paclitaxel)

Patients 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.

Drug: Paclitaxel

Given IV

Other Names:

Anzatax

Asotax

Bristaxol

Praxel

Taxol

Taxol Konzentrat

Other: Pharmacokinetic Study

Correlative studies

Other Names:

PHARMACOKINETIC

PK Study

Drug: Spleen Tyrosine Kinase Inhibitor TAK-659

Given PO

Other Names:

Spleen Tyrosine Kinase Inhibitor TAK659

syk Inhibitor TAK-659

syk Inhibitor TAK659

syk-Inhibitor TAK-659

syk-Inhibitor TAK659

TAK-659

TAK659

Outcome Measures

Primary Outcome Measures

Incidence of adverse events and serious adverse events assessed by NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 5.0 [Up to 4 years]
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.
Incidence and grade of adverse events assessed by NCI CTCAE version 5.0 [Up to 4 years]
Will assess incidence and grade of adverse events (clinical manifestations and laboratory tests) with particular attention to >= grade 2 adverse events over time by dose.
Maximum tolerated dose [Up to 28 days]
Defined according to the 3+3 design. Deaths during the study will be documented.

Secondary Outcome Measures

Dose-limiting toxicity [Up to 28 days]
Categorization of response based on Response Evaluation Criteria in Solid Tumors 1.1 [Up to 4 years]
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.
Minimum detectable effect size [Baseline up to 28 days post-treatment]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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