Soft-tissue Sarcoma
Conditions
Keywords
TAK-228, MLN0128, mTOR
Brief summary
This is an open-label phase II study of TAK-228 for patients ≥ 18 years of age with complex genomic sarcomas exhibiting Phosphoinositide-3 Kinase (PI3K) pathway dysregulation. Patients must have surgically unresectable or metastatic disease that is refractory to at least one prior line of therapy (not including neoadjuvant or adjuvant therapy in a curative setting). Patients disease must also have evidence of progression prior to enrollment. The purpose of this study is to determine the antitumor activity in this group of patients. Patients must meet all eligibility criteria as detailed in section 10. A total of up to 33 patients will be included in the study. Patients will undergo screening evaluations to determine eligibility within 28 days of the first dose. All patients will be required to submit baseline tumor samples for analysis. Patients who have had their tumors tested commercially for PI3K/ AKT/mechanistic Target of Rapamycin (mTOR) alterations will be assessed on a case by case basis for eligibility and for determination as to whether additional tissue is required. TAK-228 will be administered orally at 3 mg daily for a 21 day cycle. Clinical and laboratory assessments will be made on day 1 of each cycle. Disease will be assessed by comparing unidimensional tumor measurements on pre and peritreatment imaging (CT or MRI) after weeks 6, 12, 18 and every 12 weeks thereafter. Response will be assessed according to RECIST 1.1. Therapy will continue until disease progression or unacceptable toxicity or withdrawal of consent.
Interventions
DRUGTAK-228
TAK-228 is a novel, highly selective, orally bioavailable adenosine 5' triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as the mechanistic target of rapamycin (mTOR). TAK-228 (formerly INK128) targets 2 distinct mTOR complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
Sponsors
Fox Chase Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* This trial has two step inclusion criteria. Step 1 Inclusion Criteria 1. Male or female patients 18 years or older. 2. Patients must have a diagnosis of a locally advanced or metastatic sarcoma that is progressing. The following subtypes (considered genomically complex) will be eligible: leiomyosarcoma (well differentiated or poorly differentiated), undifferentiated pleomorphic sarcoma, myxofibrosarcoma, pleomorphic rhabdomyosarcoma, pleomorphic liposarcoma, malignant peripheral nerve sheath tumor, angiosarcoma or extraskeletal osteosarcoma. Other potentially genomically complex Soft Tissue Sarcomas (STS) subtypes may be included on a case-by-case basis after discussion with the principal investigator. 3. Measurable disease by RECIST 1.1 criteria (at least one target lesion outside of previous radiation fields or progressed within a previous radiation field), described in detail in section 15. 4. Progression of disease by radiographic imaging (10% increase in size by RECIST v1.1 within 6 months of registration) or presence of new lesions. 5. Must have received at least 1 prior systemic therapy for advanced disease (does not include adjuvant/neoadjuvant therapy in a curative setting). 6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. 7. Adequate contraception as follows: For women: Postmenopausal for at least 1 year before the screening visit, OR Surgically sterile, OR If they are of childbearing potential, agree to practice 1 effective method of contraception, and 1 additional (barrier) method, at the same time, from the time of signing the informed consent through 90 days (or longer, as mandated by local labeling \[eg. United Surgical Partners Internationals (USPI), Summary of Product Characteristics (SmPC), etc;\]) 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 patient (Periodic abstinence \[e.g, calendar, ovulation, symptothermal, postovulation methods\] and withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) Highly effective methods: Intra-uterine devices (IUD) Hormonal (birth control pills/oral contraceptives, injectable contraceptives, contraceptive patches, or contraceptive implants) Other effective Methods: Latex Condoms Diaphragm with spermicide; Cervical cap;Sponge For men, even if surgically sterilized (ie, status post-vasectomy), they must: Agree to practice highly effective barrier contraception during the entire study treatment period and through 120 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 patient (Periodic abstinence \[e.g, calendar, ovulation, symptothermal, postovulation methods for the female partner\] and 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 sperm during the course of this study or 120 days after receiving their last dose of study drug 8. Screening clinical laboratory values as specified below: a) Bone marrow reserve consistent with: i. absolute neutrophil count (ANC) ≥ 1.5 x 10(9)/L; ii. platelet count ≥ 100 x 10(9)/L; iii. hemoglobin ≥ 9 g/dL without transfusion within 1 week preceding study drug administration b) Hepatic: i. total bilirubin ≤ 1.5 x upper limit of normal (ULN), ii. transaminases (Aspartate aminotransferase/Serum Glutamic Oxaloacetic Transaminase (AST/SGOT) and Alanine aminotransferase/Serum Glutamic Pyruvic Transaminase (ALT/SGPT) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present); c) Renal: creatinine clearance ≥ 50 mL/min based either on Cockcroft-Gault estimate or based on urine collection (12 or 24 hour); d) Metabolic: i. Glycosylated hemoglobin (HbA1c) ≤ 7.0%, ii. fasting serum glucose ≤ 130 mg/dL iii. fasting triglycerides ≤ 300 mg/dL 9. Ability to swallow oral medications. 10. 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. 11. Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met: 1. Brain metastases which have been treated 2. No evidence of disease progression for ≥ 3 months or hemorrhage after treatment 3. Off-treatment with dexamethasone for 4 weeks before administration of the first dose of TAK-228 4. No ongoing requirement for dexamethasone or anti-epileptic drugs Step 2 Inclusion Criteria: Must be met after meeting step1inclusion and
Exclusion criteria
. 1\. Tumor must have dysregulation of the PI3K/AKT/mTOR pathway. For the purposes of this study, patients must have either PTEN protein or genomic loss, or phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA)/ Phosphatase and tensin homolog (PTEN) mutation. Patients must be willing to provide sufficient archival tissue. If this is not available fresh tumor for biopsy is required. In the event that a patient has had tumor analyzed for PTEN/PIK3CA status through commercial means, their eligibility and need for additional tissue will be determined on a case by case basis by the principle investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Progression Free Survival Rate With TAK-228 in Sarcoma Patients With PI3K/AKT/mTOR Pathway Dysregulation | 12 weeks post-treatment | Progression free rate will be determined by determining the number of patients with complete response, partial response and stable disease |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Rate of Toxicity of TAK-228 in This Patient Population as Per Common Terminology Criteria for Adverse Events (CTCAE)v4.03 Criteria. | 1 year | Toxicity will be assessed by calculating number of participants experiencing adverse events as per CTCAEv4.03 criteria |
| The Objective Response Rate (ORR) of TAK-228 in This Patient Population. | upto 4 years | Objective response rate will be defined as patients with complete response and partial response. As per RECIST v1.1 guidelines, complete response is defined as the disappearance of all measurable lesions, and partial response is defined as \>=30% decrease in sum of diameters of target lesions compared to the baseline sum of diameters. |
| Progression Free Survival in This Patient Population. | upto 4 years | Progression Free Survival, defined as the time from initiation of treatment until disease progression will be calculated. |
| Overall Survival Rate in This Patient Population | upto 4 years | Overall Survival, defined as the time from initiation of treatment until death from any cause will be calculated. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TAK-228 Treatment Patients with complex genomic sarcomas exhibiting PI3K pathway dysregulation will be treated with TAK-228
TAK-228: TAK-228 is a novel, highly selective, orally bioavailable adenosine 5' triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as the mechanistic target of rapamycin (mTOR). TAK-228 (formerly INK128) targets 2 distinct mTOR complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Grantor stopped supply of drugs | 6 |
Baseline characteristics
| Characteristic | TAK-228 Treatment |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 53 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 2 Participants |
| Tumor type Extraskeletal osteosarcoma | 1 Participants |
| Tumor type Leiomyosarcoma | 4 Participants |
| Tumor type Soft tissue sarcoma | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 6 |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 2 / 6 |
Outcome results
Primary
The Progression Free Survival Rate With TAK-228 in Sarcoma Patients With PI3K/AKT/mTOR Pathway Dysregulation
Progression free rate will be determined by determining the number of patients with complete response, partial response and stable disease
Time frame: 12 weeks post-treatment
Population: Insufficient number of patients accrued for a meaningful analysis. No data collected from any participant.
Secondary
Overall Survival Rate in This Patient Population
Overall Survival, defined as the time from initiation of treatment until death from any cause will be calculated.
Time frame: upto 4 years
Population: Insufficient number of patients accrued for a meaningful analysis. No data collected from any participant.
Secondary
Progression Free Survival in This Patient Population.
Progression Free Survival, defined as the time from initiation of treatment until disease progression will be calculated.
Time frame: upto 4 years
Population: Insufficient number of patients accrued for a meaningful analysis. No data collected from any participant.
Secondary
The Objective Response Rate (ORR) of TAK-228 in This Patient Population.
Objective response rate will be defined as patients with complete response and partial response. As per RECIST v1.1 guidelines, complete response is defined as the disappearance of all measurable lesions, and partial response is defined as \>=30% decrease in sum of diameters of target lesions compared to the baseline sum of diameters.
Time frame: upto 4 years
Population: Insufficient number of patients accrued for a meaningful analysis. No data collected from any participant.
Secondary
The Rate of Toxicity of TAK-228 in This Patient Population as Per Common Terminology Criteria for Adverse Events (CTCAE)v4.03 Criteria.
Toxicity will be assessed by calculating number of participants experiencing adverse events as per CTCAEv4.03 criteria
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TAK-228 Treatment | The Rate of Toxicity of TAK-228 in This Patient Population as Per Common Terminology Criteria for Adverse Events (CTCAE)v4.03 Criteria. | 6 Participants |