Assessing the safety and effectiveness of vactosertib for osteosarcoma

Inclusion Criteria

Subjects must meet all the following inclusion criteria to be eligible for enrollment:

Informed Consent/Assent 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 ≥12 years at the time of screening

Type of Subject and Disease Characteristics

1. Subjects may be male or female, with adolescents aged 12 to 17 years and adults aged 18 years or older, as defined by applicable country-specific legal age classifications. No large studies have evaluated the use of vactosertib in younger pediatric subjects, for this reason, children younger than 12 years of age are excluded from this study.
2. Subjects must have clinical, radiologic, and histologic confirmation of Osteosarcoma (OSa), which must be documented.
3. Subjects must have measurable disease according to RECIST 1.1, diagnosed as recurrent, refractory or progressive osteosarcoma, and must have no available standard therapy.
4. 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 with the exception of alopecia, anorexia, bone pain, and tumor pain prior to entering this study.
5. Myelosuppressive chemotherapy: Must have adequate recovery of counts from previous treatment prior to entry onto this study.
6. Inclusion criteria include adequate renal function, ECOG performance status 0-2, and either Lansky performance status of 50-100% (\<16 years old), or Karnofsky performance status 50-100% (≥16 years old). Subjects 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.
7. 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. Albumin (serum or plasma) \> 2 g/dL c. Adequate cardiac function defined as: i. Ejection fraction of ≥ 50% by echocardiogram or MUGA
8. 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 (per country).
9. Renal laboratory inclusion:
10. Relapsed osteosarcoma (first, second, third or any subsequent relapse, subject who have recovered from chemotherapy and any other investigational product/agent treatment, radiotherapy or surgical procedure), with histological confirmed diagnosis of osteosarcoma at original presentation, and progressive disease documented by imaging within 3 months of entry into the trial.
11. Subjects with a life expectancy of at least 3 months.

Exclusion Criteria

The subject must be excluded from participating in the trial if:

1. Subjects who have moderate or severe cardiovascular disease

   1. 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
   2. Subjects who have major abnormalities at the Investigator's discretion based on electrocardiogram (ECG)and Doppler ECHO and MUGA results at screening or within 14 days before screening. QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms in both male and female calculated from 12-lead ECGs.
   3. 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)
   4. Subjects who have risk factors for ascending aortic aneurysm such as genetic disorder and trauma and risk factors for aortic stenosis
   5. Subjects who have a history of heart or aorta surgery
2. Subjects who have clinically significant gastrointestinal bleeding within 4 weeks before screening
3. Subjects who have a known history or suspected hypersensitivity to any excipients of the investigational product.
4. Subjects who have received prior treatment targeting the signaling pathway of TGF-β
5. Subjects who are currently using or planning to use prohibited medications with vactosertib. For these medications, a washout period equivalent to at least 5 half-lives prior to the first dose of the investigational product is recommended.

   1. 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.)
   2. Drugs that are exclusively or primarily eliminated by UDP glucuronyltransferase (UGT) 1A1 (UGT1A1)
   3. 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
6. Subjects who are unable to swallow tablets
7. Subjects who have a history of or are suspected of drug abuse
8. 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 subjects 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.
9. Subjects, in the opinion of the Investigator, who are unsuitable to participate in the study
10. Subjects who have received an investigational product or used an investigational medical device within 28 days prior to screening, or within 5 half-lives of the investigational product (whichever is longer), or who are currently participating in another clinical trial.

    Note: Subjects in follow-up phase of a previous clinical trial may be enrolled in this study if more than 4 weeks have passed since the last administration.
11. Subjects who have not completed an adequate washout period prior to the first dosing of the investigational product will be excluded (\< 3 weeks for chemotherapy, \< 6 weeks for curative radiotherapy, or \< 2 weeks for palliative radiotherapy)
12. Subjects who are severely underweight and, in the opinion of the investigator, unsuitable for study treatment, according to country-specific criteria.
13. 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.
14. HIV-positive subjects including those receiving antiretroviral therapy, are ineligible because of the risk for developing a lethal infection when treated with immunosuppressive therapy.
15. Subject with active or acute infection confirmed at screening.
16. Non-metastatic osteosarcoma (OSa) for whom standard therapy is available at the time of the study may be excluded.
17. Subject with chronic use of corticosteroids or other immunosuppressive agents. Note: High dose is defined as a prescription of \>5 mg oral prednisolone and long term as duration of treatment \>1 month (based on NICE. Corticosteroids - oral (accessed Apr 2017).