Study to Assess Safety and Efficacy of Vactosertib in Adolescents and Adults With Recurrent, Refractory or Progressive Osteosarcoma

Study Overview
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Brief Summary
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MP-VAC-209 is a Phase I/II, open label, single arm, multi-center study to assess safety, tolerability, and antitumor activity of vactosertib as a single agent in adolescents and adults with recurrent, refractory, or progressive osteosarcoma. Vactosertib is given orally, twice a day, to people 14 years of age and older who meet the criteria for study enrollment.

Detailed Description
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Overall Design: This is a Phase I/II, open label, single arm, proof of concept, multi-center study to assess safety, tolerability, pharmacokinetics and antitumor activity of vactosertib as a Single Agent in Adolescents and Adults with Recurrent, Refractory or Progressive Osteosarcoma. During the Phase I part of the trial, dose limiting toxicity will be determined by a standard 3+3 dose escalation design. Data from the Phase I part of the trial will be reviewed by the Data Safety and Toxicity Committee before transitioning to Phase II. During Phase I, at least 6 patients will be enrolled at the maximum tolerated dose (MTD) level. To evaluate efficacy during Phase II, 42 patients will be enrolled at the maximum dose level; this includes the patients enrolled at this dose level during Phase I. This study has been designed to allow for an investigation of the optimal dose of vactosertib. This clinical study consists of two parts: Phase I: Vactosertib dose-escalation study: To determine the recommended phase II dose (RP2D) and evaluate the safety and tolerability of vactosertib in subjects with recurrent, refractory, or progressive OS; and ● Initially, the dose limiting toxicity and maximum tolerated dose (MTD) of vactosertib in adolescence and young adult age population (14 and older) will be evaluated using a standard 3 + 3 design for adult equivalent doses of 150 mg BID, 5 days on and two days off, 200 mg BID, five days on and two days off and 250 mg, BID, five days on and two days off for one week. Phase I/II: Vactosertib PK/PD and efficacy study: to characterize the pharmacokinetics (PK) of vactosertib and to determine the efficacy of vactosertib by evaluating the antitumor activity of vactosertib, the overall response rate of subjects treated with vactosertib and by assessing the effect of vactosertib on Pharmacodynamic (PD) biomarkers on baseline and serial tumor tissues and blood samples. ● Once the safety and MTD of vactosertib in adolescence and young adult age population (14 and older) is established, the study will then enroll a total of 42 evaluable patients, including the patients enrolled at MTD level during Phase I with the following treatment regimen: o Vactosertib twice a day, five days on and two days off in a four-week cycle with confirmed treatment dose as per run in (phase I). Number of patients: Phase I: At least 6 and Phase II: 42 Treatments and Treatment Duration: Vactosertib will be administered orally 5 days per week (5D/W) approximately at the same time twice daily (BID; morning and evening approximately 12 hours apart). Vactosertib should be taken orally with food.

Official Title
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A Phase I/II, Open-label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of Vactosertib as a Single Agent in Adolescents and Adults With Recurrent, Refractory or Progressive Osteosarcoma

Conditions
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Osteosarcoma

Intervention / Treatment
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* Drug: Vactosertib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Age ≥14 years at the time of screening Type of Patient and Disease Characteristics Subjects may be male or female and must be equal to or greater than 14 years of age. No large studies have evaluated the use of vactosertib in younger pediatric patients, for this reason, children younger than 14 years of age are excluded from this study. Subjects must have histologic verification of Osteosarcoma (OS) Subjects must have measurable disease per RECIST 1.1 (Appendix B), documented by clinical, radiographic and histologic criteria, and have progressed, relapsed or become refractory to conventional therapy. Subjects must have recovered from the acute toxic effects with ≤ Grade 1 as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 of all prior chemotherapy and immunotherapy except for alopecia, anorexia, bone pain, and tumor pain prior to entering this study. Myelosuppressive chemotherapy: Must have adequate recovery of counts from previous treatment prior to entry onto this study. Inclusion criteria include adequate renal function, absence of concurrent active/acute infection, Lansky performance status of 50-100% (>16 years old), ECOG performance status 0-2, or Karnofsky performance status 50-100% (>16 years old). Chronic use of corticosteroids or other immunosuppressive agents and non-metastatic osteosarcoma (OS) for whom standard therapy are possible at the time of the study may be excluded. Patients who are unable to walk because of paralysis, but who are up in a wheelchair will be considered ambulatory for the purpose of assessing the performance score. Subjects must have normal organ and marrow function as defined below: a. Adequate bone marrow function defined as: i. Peripheral absolute neutrophil count (ANC) ≥ 750/mcL ii. Platelet count ≥ 75,000/mcL (transfusion independent) iii. Hemoglobin ≥ 8.0 g/dL (may receive packed red blood cell transfusions) b. Adequate liver function defined as: i. Total bilirubin ≤ 1.5 times the upper limit of normal for age ii. AST (SGOT) and ALT (SGPT) 2.5 X institutional upper limit of normal iii. Serum albumin > 2 g/dL c. Adequate cardiac function defined as: i. Ejection fraction of ≥ 50% by echocardiogram Subjects must have the ability to understand and the willingness to sign a written informed consent document if ≥ 18 years of age and an assent document if < 18 years of age Body weight >30 kg Male or Female - Exclusion Criteria: Subjects who have moderate or severe cardiovascular disease Subjects who have uncontrolled intercurrent illness, including but not limited to, ongoing or active infection requiring systemic therapy, symptomatic congestive heart failure (New York Heart Association Class III/IV), uncontrolled hypertension (≥150/90mmHg), unstable angina pectoris or myocardial infarction (≤ 6 months prior to screening), uncontrolled cardiac arrhythmia, clinically significant cardiac valvulopathy requiring treatment, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the subject to give written informed consent Subjects who have major abnormalities at the Investigator's discretion based on electrocardiogram (ECG)and Doppler ECHO results at screening or within 14 days before screening. QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥450 ms in male and ≥470 ms in female calculated from 12-lead ECGs Subjects who have increase in brain natriuretic peptide (BNP) or increase in troponin (over 99th percentile upper reference limit) at Screening (based on the normal range of relevant study center) Subjects who have risk factors for ascending aortic aneurysm such as genetic disorder and trauma and risk factors for aortic stenosis Subjects who have a history of heart or aorta surgery Subjects who have clinically significant gastrointestinal bleeding within 4 weeks before screening Subjects who have a known history or suspected hypersensitivity to any excipients of the investigational product or combination drug(s) Subjects who have received prior treatment targeting the signaling pathway of TGF-β Subjects who have a disease or condition that affects the mechanism of the investigational product, or are currently using or planning to use: Drugs that are exclusively or primarily eliminated by cytochrome P-450 isozyme (CYP) including CYP1A2, CYP2D6, CYP2B6, or CYP3A4 (Concurrent use of drugs that are known potent CYP3A4 inducers including but not limited to Phenytoin, Rifampin, and St. John's wort. Concurrent use of foods that are known strong CYP3A4 inhibitors including but not limited to grapefruit juice, Itraconazole, Ketoconazole, Lopinavir/ritonavir, Mibefradil, and Voriconazole. The topical use of these medications (if applicable), such as 2% ketoconazole cream, may be allowed.) Drugs that are exclusively or primarily eliminated by UDP glucanosyltransferase (UGT) 1A1 (UGT1A1) Drugs that are substrates for the drug transporter multidrug resistance protein 1 (MDR1) have a narrow therapeutic window or are strong inhibitors of drug transporter MDR1 Subjects who are unable to swallow tablets Subjects who have a history of or are suspected of drug abuse Female subjects of child-bearing potential who have a positive result on a pregnancy test at screening or are unable to agree to use an effective barrier method of birth control to avoid pregnancy during the study period (e.g., sterilization, intrauterine contraceptive device, combination of oral contraception and barrier contraception, combination of other hormone delivery systems and barrier contraception, contraceptive cream, combination of cream, jelly, or form and diaphragm or condom). Male patients of reproductive potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 90 days after the last dose of study therapy. Subjects, in the opinion of the Investigator, who are unsuitable to participate in the study Subjects who were treated with other investigational products within 28 days before screening or within a period shorter than 5-times the half-life of the investigational product Subjects currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment Note: Subjects who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. Subjects taking prohibited medications when using vactosertib as following (Refer to Appendix D). A minimal washout period of 5 half-lives for the following drugs is recommended prior to the first dosing Subjects with severe hypersensitivity to vactosertib and/or any of its excipient Subjects with a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. HIV-positive subjects and HIV-positive subjects on antiretroviral therapy are ineligible because of the risk for developing a lethal infection when treated with immunosuppressive therapy.

Ages Eligible for Study
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Minimum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>Single arm, open-label, no blinding or randomization procedure will be involved. | Drug: Vactosertib<br>* Vactosertib is given twice a day, five days on and two days off in four-week cycles. Vactosertib is a transforming growth factor-beta (TGF-β) type 1 receptor inhibitor.<br>* Other names: TEW-7197;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose finding associated with the overall nature and severity of AEs associated with treatment. | Maximum tolerated dose (MTD) and recommended dose (RD) | Assessment of adverse events and laboratory abnormalities. through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival. | Overall survival (1 year) calculated from date of enrollment to the dates of documented evidence of progression or death up to 12 months. | Acquiring the measures associated with phase I/phase II primary endpoints. | 
| Time to response(TTR) | To evaluate the time to response(TTR) from Vactosertib treatment to show PR or CR. To characterize the pharmacokinetics(PK) of Vactosertib to 6 patients assigned to dose- escalation phase and the firsts 12 patients assigned to the dose expansion phase. | Post two cycle of treatment, evaluation. through study completion, an average of 1 year. |