Sarcoma, Ewing
Conditions
Brief summary
Ewing sarcoma is characterized by genomic rearrangements resulting in over-expression of ets family transcription factors driving tumor progression. TK216 is designed to inhibit this effect by inhibiting downstream effects of the EWS-FLI1 transcription factor. This study is a first in human study of TK216 in subjects with Ewing sarcoma. The study is designed to establish initial safety and efficacy data in monotherapy and in combination with vincristine to assess the potential of TK216 for further development.
Detailed description
The study has been expanded to explore single agent TK216 for longer treatment duration. Approximately 26 patients will be enrolled in this Cohort. Please note: This study has been terminated and is no longer enrolling patients.
Interventions
DRUGTK216
Inhibitor of protein-protein interactions of EWS-FLI1 fusion protein
Sponsors
Oncternal Therapeutics, Inc
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
8 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1\. Major Inclusion Criteria (for all Study Parts or protocol versions unless specifically noted): Patients who meet the following inclusion criteria will be eligible to participate in this study: 1. Willing and able to provide written IRB/IEC-approved Informed Consent. For patients \< 18 years of age, their parent or legal guardian must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines. 2. Have histologically or cytologically confirmed diagnosis of Ewing sarcoma (including ESFT) with relapsed or refractory disease 1. who have failed standard therapy and for whom no known curative therapy exists (For Parts 1-3), OR 2. patients with metastatic disease who had standard chemotherapy at the time of diagnosis (For Part 4) (NOTE: as of Protocol version 7, pathology reports and slides or blocks should be available for review or additional testing. If not available, site must discuss with Sponsor.) 3. Measurable disease according to RECIST version 1.1. Measurable disease can be verified from a previously documented CT scan or MRI as long as no anti-cancer treatments have been administered in the interim. 4. Must have a central venous catheter in place prior to initiating infusion of study drug. 5. Prior cancer therapy: 1. Patients may have received any number of prior therapy regimens (For Parts 1-3) OR 2. Patients may have received no more than 5 prior systemic regimens. At the time of treatment initiation, at least 2 weeks or 5 half-lives, whichever is longer, must have elapsed since prior cytotoxic chemotherapy. At least 7 days must have elapsed since completion of any prior non-cytotoxic cancer therapy (For Part 4). 6. Prior radiotherapy is allowed 1. If ≥ 2 weeks have elapsed for local palliative XRT (small port); ≥ 6 months must have elapsed if prior total body irradiation, craniospinal XRT or if \> 50% radiation of the pelvis; \> 6 weeks must have elapsed if other substantial bone marrow radiation. Patients who have received brain irradiation must have completed whole brain radiotherapy and/or gamma knife at least 4 weeks prior to enrollment (For Parts 1-3) OR 2. If ≥ 4 weeks has elapsed for radiation therapy (RT); ≥ 6 months must have elapsed if prior total body irradiation, craniospinal RT or if \> 50% radiation of the pelvis; \> 6 weeks must have elapsed if other substantial bone marrow radiation. Patients who have received brain irradiation must have completed whole brain radiotherapy and/or gamma knife at least 4 weeks prior to enrollment (For Part 4). 7. Stem Cell Transplant or Rescue without TBI: No evidence of active graft vs. host disease and ≥ 3 months must have elapsed since transplant. 8. Patients with controlled asymptomatic CNS involvement are allowed. 9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 in patients ≥17 years old; or Karnofsky/Lansky \>50 in patients \<16 years old. 10. Age: a. Cohort 1: Patient's age \>18 years old. b. Cohorts 2-6: Patients must be \> 12 years old. c. Cohorts 7-10: Patients must be ≥ 10 years old. d. Cohort 11: Patient's age ≥ 8 years (For Part 4) 11. Life expectancy of at least 3 months. 12. Adequate organ function as measured by baseline laboratory values. 13. Cardiac ejection fraction \> 50% or shortening fraction \> 28%. 14. Females of child-bearing potential must have a negative pregnancy test (within 7-days of starting treatment) during screening and subjects must be willing to use effective contraception. be neither breastfeeding nor intending to become pregnant during study participation. Females of childbearing potential must agree to avoid pregnancy during the study and commit to abstinence from heterosexual intercourse or agree to use two methods of birth control (one highly effective method and one additional effective method) at least 4 weeks before the start of protocol therapy, for the duration of study participation, and for 6 months after the last dose of TK216. 15. Males with partner(s) of childbearing potential must take appropriate precautions to avoid fathering a child from the screening period until 90 days after receiving the last dose of TK216. They must commit to abstinence from heterosexual intercourse or agree to use appropriate barrier contraception. 16\. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures. Major
Exclusion criteria
Patients will not be enrolled if they meet any one of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | 36 months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions and pathologic lymph nodes; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions, no new lesions, and no progression of non-target lesions; Overall Response (OR) = CR + PR. |
Countries
United States
Participant flow
Recruitment details
85 subjects were enrolled in this study across eight North American centers. The pathologic diagnoses were confirmed at each enrolling center. Most patients were heavily pretreated, with the median number of prior therapies being 3.0 (range, 1-10). The gender and ethnicity of the enrolled patients matched ES's prevalence in the U.S. population.
Pre-assignment details
Once an appropriate patient has been identified, a 30-day screening period began and evaluated eligibility. The study was executed in several Parts: Part 1: Dose Escalation Segment (Cohorts 1-6) Part 2: Schedule Escalation Segment (Cohorts 7-9) Part 3: Expansion Segment (Cohort 10) Part 4: Dose and Schedule Evaluation Segment (Cohort 11) Note: For purposes of result summaries, Cohorts 1-8 pooled, Cohorts 9 & 10 pooled, and Cohort 11 will be displayed.
Participants by arm
| Arm | Count |
|---|---|
| 18 mg/m^2 (7 Days) Dose Escalation Segment (Cohorts 1-6) was an open label, 3+3 patient enrollment scheme, sequential allocation, dose finding allocation of the sequential allocation of TK216 monotherapy. The length of TK216 infusion for all dose escalation cohorts was 7 days. A lower intermediate dose of 220mg/m2 /day for 7 days was determined to be the maximum tolerated dose (MTD) for the 7-day continuous infusion of TK216. | 3 |
| 36 mg/m^2 (7 Days) Dose Escalation Segment (Cohorts 1-6) was an open label, 3+3 patient enrollment scheme, sequential allocation, dose finding allocation of the sequential allocation of TK216 monotherapy. The length of TK216 infusion for all dose escalation cohorts was 7 days. A lower intermediate dose of 220mg/m2 /day for 7 days was determined to be the maximum tolerated dose (MTD) for the 7-day continuous infusion of TK216. | 3 |
| 72 mg/m^2 (7 Days) Dose Escalation Segment (Cohorts 1-6) was an open label, 3+3 patient enrollment scheme, sequential allocation, dose finding allocation of the sequential allocation of TK216 monotherapy. The length of TK216 infusion for all dose escalation cohorts was 7 days. A lower intermediate dose of 220mg/m2 /day for 7 days was determined to be the maximum tolerated dose (MTD) for the 7-day continuous infusion of TK216. | 3 |
| 144 mg/m^2 (7 Days) Dose Escalation Segment (Cohorts 1-6) was an open label, 3+3 patient enrollment scheme, sequential allocation, dose finding allocation of the sequential allocation of TK216 monotherapy. The length of TK216 infusion for all dose escalation cohorts was 7 days. A lower intermediate dose of 220mg/m2 /day for 7 days was determined to be the maximum tolerated dose (MTD) for the 7-day continuous infusion of TK216. | 3 |
| 200 mg/m^2 (10 Days) Dose Escalation Segment (Cohorts 1-6) was an open label, 3+3 patient enrollment scheme, sequential allocation, dose finding allocation of the sequential allocation of TK216 monotherapy. The length of TK216 infusion for all dose escalation cohorts was 7 days. A lower intermediate dose of 220mg/m2 /day for 7 days was determined to be the maximum tolerated dose (MTD) for the 7-day continuous infusion of TK216. | 4 |
| 200 mg/m^2 (14 Days) Dose Escalation Segment (Cohorts 1-6) was an open label, 3+3 patient enrollment scheme, sequential allocation, dose finding allocation of the sequential allocation of TK216 monotherapy. The length of TK216 infusion for all dose escalation cohorts was 7 days. A lower intermediate dose of 220mg/m2 /day for 7 days was determined to be the maximum tolerated dose (MTD) for the 7-day continuous infusion of TK216. | 4 |
| 220 mg/m^2 (7 Days) Schedule Escalation Segment (Cohorts 7-9) was an open label, 3+3 patient enrollment scheme, sequential allocation of the increase in length of infusion of TK216 monotherapy. Following the first two cycles, vincristine could be added as tolerated up to 2mg on the first day of each cycle. The recommended Phase 2 dose (RP2D) was determined to be 200mg/m2 /day for 14 days followed by a 14-day recovery period, per 28-day cycle | 3 |
| 220 mg/m^2 (10 Days) Schedule Escalation Segment (Cohorts 7-9) was an open label, 3+3 patient enrollment scheme, sequential allocation of the increase in length of infusion of TK216 monotherapy. Following the first two cycles, vincristine could be added as tolerated up to 2mg on the first day of each cycle. The recommended Phase 2 dose (RP2D) was determined to be 200mg/m2 /day for 14 days followed by a 14-day recovery period, per 28-day cycle | 3 |
| 288 mg/m^2 (7 Days) Schedule Escalation Segment (Cohorts 7-9) was an open label, 3+3 patient enrollment scheme, sequential allocation of the increase in length of infusion of TK216 monotherapy. Following the first two cycles, vincristine could be added as tolerated up to 2mg on the first day of each cycle. The recommended Phase 2 dose (RP2D) was determined to be 200mg/m2 /day for 14 days followed by a 14-day recovery period, per 28-day cycle | 7 |
| Expansion Cohort Expansion Segment (Cohort 10) where patients were treated with the schedule for RP2D of TK216 with vincristine 0.75 - 1.5 mg/m2 administered on the first day of each 28-day cycle | 44 |
| 175 mg/m^2 (28 Days) Dose and Schedule Evaluation Segment (Cohort 11) where patients received a starting dose of 175mg/m2 /day of TK216 intravenously by continuous infusion for 28 days per cycle. If the patient's tumor response was determined by the Investigator as inadequate after at least one protocol-specified post-baseline assessment and they were not experiencing toxicities at this dose level, the Investigator could increase the dose to 200 mg/m2/day after discussion with the Sponsor. Vincristine (0.75 to 1.5 mg/m2 up to a maximum dose of 2 mg) could be administered in parallel with the TK216 infusion following progressive disease after TK216-01 monotherapy but only after consultation with the Sponsor. | 8 |
| Total | 85 |
Baseline characteristics
| Characteristic | 18 mg/m^2 (7 Days) | Total | 175 mg/m^2 (28 Days) | Expansion Cohort | 288 mg/m^2 (7 Days) | 220 mg/m^2 (10 Days) | 220 mg/m^2 (7 Days) | 200 mg/m^2 (14 Days) | 200 mg/m^2 (10 Days) | 144 mg/m^2 (7 Days) | 72 mg/m^2 (7 Days) | 36 mg/m^2 (7 Days) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 28.0 years STANDARD_DEVIATION 5.3 | 28.9 years STANDARD_DEVIATION 13.1 | 27.0 years STANDARD_DEVIATION 10 | 29.2 years STANDARD_DEVIATION 14.6 | 23.7 years STANDARD_DEVIATION 6.3 | 24.0 years STANDARD_DEVIATION 10 | 24.7 years STANDARD_DEVIATION 8.1 | 25.5 years STANDARD_DEVIATION 7.9 | 30.0 years STANDARD_DEVIATION 9.5 | 33.3 years STANDARD_DEVIATION 10.7 | 41.3 years STANDARD_DEVIATION 12.7 | 38.7 years STANDARD_DEVIATION 28.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 7 Participants | 0 Participants | 1 Participants | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 4 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 69 Participants | 5 Participants | 41 Participants | 0 Participants | 2 Participants | 3 Participants | 4 Participants | 4 Participants | 2 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Female | 1 Participants | 29 Participants | 2 Participants | 16 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 56 Participants | 6 Participants | 28 Participants | 5 Participants | 2 Participants | 1 Participants | 3 Participants | 4 Participants | 3 Participants | 2 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 2 / 3 | 3 / 3 | 3 / 3 | 4 / 4 | 2 / 4 | 2 / 3 | 3 / 3 | 3 / 7 | 26 / 44 | 1 / 8 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 4 / 4 | 4 / 4 | 3 / 3 | 3 / 3 | 7 / 7 | 44 / 44 | 8 / 8 |
| serious Total, serious adverse events | 1 / 3 | 1 / 3 | 1 / 3 | 1 / 3 | 4 / 4 | 1 / 4 | 2 / 3 | 1 / 3 | 2 / 7 | 21 / 44 | 5 / 8 |
Outcome results
Primary
Overall Response Rate
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions and pathologic lymph nodes; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions, no new lesions, and no progression of non-target lesions; Overall Response (OR) = CR + PR.
Time frame: 36 months
Population: All Patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 18 mg/m^2 (7 Days) | Overall Response Rate | 0 Participants |
| 36 mg/m^2 (7 Days) | Overall Response Rate | 0 Participants |
| 72 mg/m^2 (7 Days) | Overall Response Rate | 0 Participants |
| 144 mg/m^2 (7 Days) | Overall Response Rate | 0 Participants |
| 200 mg/m^2 (10 Days) | Overall Response Rate | 0 Participants |
| 200 mg/m^2 (14 Days) | Overall Response Rate | 0 Participants |
| 220 mg/m^2 (7 Days) | Overall Response Rate | 0 Participants |
| 220 mg/m^2 (10 Days) | Overall Response Rate | 0 Participants |
| 288 mg/m^2 (7 Days) | Overall Response Rate | 0 Participants |
| Expansion Cohort | Overall Response Rate | 3 Participants |
| 175 mg/m^2 (28 Days) | Overall Response Rate | 0 Participants |