Myelodysplastic Syndromes
Conditions
Brief summary
This is a Phase 2 randomized, open-label, two-stage study designed to investigate the antitumor activity of tipifarnib in approximately 36 eligible subjects with MDS who have no known curative treatment. Subjects will be randomized to receive tipifarnib orally with food according to one of 2 treatment regimens.
Detailed description
This Phase 2 study will investigate the antitumor activity in terms of ORR of tipifarnib in approximately 36 eligible subjects with MDS who have no known curative treatment. Eligible subjects may have received no more than 2 prior systemic regimens. Subjects will be randomized to receive tipifarnib orally with food according to one of 2 dose regimens. In the absence of unmanageable toxicities, subjects may continue to receive tipifarnib treatment until disease progression. Disease assessments will be performed at screening and at least once every approximately 12 weeks starting at the end of cycle 3. Determination of ORR will be assessed by the Investigator according to the MDS International Working Group (IWG) criteria (Cheson 2006). Upon disease progression, all subjects in the study will be followed approximately every 12 weeks for survival and the use of subsequent therapy until either death or 12 months after accrual of the study has been completed, whichever occurs first.
Interventions
DRUGTipifarnib
Oral tablet
Sponsors
Kura Oncology, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject is at least 18 years of age. * Documented pathological evidence of MDS as defined by the World Health Organization (WHO) criteria. * Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. * Subjects have no known curative treatment. * Subject is willing and able to comply with scheduled visits, treatment plans, laboratory tests and other procedures (including bone marrow assessments). * At least 1 week since the last systemic therapy regimen prior to Cycle 1 Day 1. Subjects must have recovered to NCI CTCAE v. 4.03 \< Grade 2 from all acute toxicities (excluding Grade 2 toxicities that are not considered a safety risk by the Sponsor and Investigator) or toxicity must be deemed irreversible by the Investigator. * Acceptable hematological function: 1. Absolute neutrophil count \< 1000/mm3 2. Platelet count \> 20,000/mm3 * Acceptable liver function: 1. Total or direct bilirubin ≤ 1.5 times upper limit of normal (x ULN); does not apply to subjects with Gilbert's syndrome diagnosed as per institutional guidelines. 2. AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN. * Acceptable renal function with serum creatinine ≤ 1.5 x ULN or a calculated creatinine clearance ≥ 60 mL/min using the Cockcroft-Gault or Modification of Diet in Renal Disease formulas. * Female subjects must be: 1. Of non-child-bearing potential (surgically sterilized or at least 2 years post-menopausal); or 2. If of child-bearing potential, subject must use a highly effective method of contraception, such as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner or sexual abstinence. Both females and male subjects with female partners of child-bearing potential must agree to use a highly effective method of contraception for 2 weeks prior to screening, during, and at least 4 weeks after last dose of trial medication. Female subjects must have a negative serum or urine pregnancy test within 72 hours prior to start of trial medication. 3. Not breast feeding at any time during the study. * Written and voluntary informed consent understood, signed and dated.
Exclusion criteria
* Known prior progression to acute myeloid leukemia (AML), defined by at least 20% blasts in the blood or bone marrow. * Myelodysplastic or myeloproliferative syndrome other than MDS. * More than two prior systemic regimens for MDS. Prior systemic regimens are those that are considered standard of care for the treatment of MDS, have been received at standard doses for at least one full treatment cycle and exclude ESA. * Prior cytoreductive therapy for blast reduction. * Participation in any interventional study within 1 week or 5 half lives (whichever is longer) of Cycle 1 Day 1. * Ongoing treatment with an anticancer agent for MDS not contemplated in this protocol. * Prior treatment (at least 1 full treatment cycle) with a farnesyltransferase inhibitor. * Clinically significant anemia due to iron, B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding. If marrow stain for iron is not available, the transferrin saturation (iron/total iron binding capacity Fe/TIBC) must be \>20% or serum ferritin must be \>100 ng/dL. * Active coronary artery disease requiring treatment, myocardial infarction within the prior year, New York Heart Association grade III or greater congestive heart failure, cerebro-vascular attack within the prior year, or current serious cardiac arrhythmia requiring medication except atrial fibrillation. * Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, without complete recovery. * Active, concurrent malignancy requiring radiation, chemotherapy, or immunotherapy (excluding non-melanoma skin cancer, adjuvant hormonal therapy for breast cancer and hormonal treatment for castration sensitive prostate cancer). * Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy. Known infection with human immunodeficiency virus (HIV), or an active infection with hepatitis B or hepatitis C. * Subjects who have exhibited allergic reactions to tipifarnib, or structural compounds similar to tipifarnib or to its excipients. * Concomitant disease or condition that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study. * The subject has legal incapacity or limited legal capacity. * Significantly altered mental status that would limit the understanding or rendering of informed consent and compliance with the requirements of this protocol. Unwillingness or inability to comply with the study protocol for any reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 1 year | ORR was assessed by the investigator and included complete response (CR), partial response (PR), marrow complete remission (MR), and hematologic improvement (HI) according to the MDS International Working Group (IWG) criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Transfusion Independence | 1 year | Duration of transfusion independence is defined as the period of time where participants achieved transfusion independence. |
| Hematologic Improvement | 1 year | Number of subjects who experienced hematologic improvements (erythroid response, platelet response, or neutrophil response). |
| Duration of Response | 1 year | Duration of response is defined as the number of days from the start date of response (whichever response is achieved first) to the first date that progressive disease is objectively documented. |
| Rate of Transfusion Independence | 1 year | Rate of transfusion independence is defined as number of participants with transfusion independence at any response assessment over 1 year. |
| Overall Survival (OS) at 1 Year | 1 year | OS is defined as the time (in months) from enrollment to occurrence of death due to any cause within 1 year (approximately 4 time intervals for disease assessments) of either first administration of tipifarnib or the last disease assessment. |
| Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | 1 year | TEAEs are defined as AEs that started on or after the first dose of study drug and within approximately 30 days of the last administration of study drug. AEs were summarized by the number and percentage of subjects who experienced the event, according to system organ class and preferred term. A subject reporting multiple cases of the same AE will be counted once within each system organ class and similarly counted once within each preferred term. |
| Progression-free Survival (PFS) at 1 Year | 1 year | PFS is defined as the time (in months) from enrollment to either first observation of progressive disease or occurrence of death due to any cause within 1 year (approximately 4 time intervals for disease assessments) of either first administration of tipifarnib or the last disease assessment. |
Countries
United States
Participant flow
Recruitment details
Subjects affected by myelodysplastic syndromes (MDS) were recruited across 2 sites in the United States between June 2016 and August 2018.
Pre-assignment details
This study included a screening period, treatment period (28-day cycles until disease progression), end of treatment visit, follow-up visit (for subjects who terminated treatment for reasons other than death or disease progression), and follow-up contact (upon disease progression, all subjects were followed approximately every 12 weeks for survival and use of subsequent therapy until either death or accrual in the subject's study cohort was completed, whichever occurred first).
Participants by arm
| Arm | Count |
|---|---|
| Original Cohort Subjects prior to Amendment 3 were considered to be the Original Cohort. Prior to Amendment 3 this was a non-randomized study with 900 twice daily (BID) (Days 1-7 and 15-21) in 28 day cycles, allowing for adjustments in dosing/schedule based on patient tolerability. | 14 |
| Regimen 1: Tipifarnib 600 mg BID for 7 days on Days 1-7 in 28 day cycles (ie, 1 week on/3 weeks off). | 1 |
| Regimen 2: Tipifarnib 300 mg BID for 21 days on Days 1-21 in 28 day cycles (ie, 3 weeks on/1 week off). | 1 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 | 0 |
| Overall Study | Disease Progression | 1 | 0 | 0 |
| Overall Study | Physician Decision | 9 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Regimen 2: Tipifarnib | Regimen 1: Tipifarnib | Original Cohort |
|---|---|---|---|---|
| Age, Continuous | 71.4 years STANDARD_DEVIATION 7.2 | 68.9 years | 76.6 years | 71.2 years STANDARD_DEVIATION 7.5 |
| ECOG Performance Status 0 | 13 Participants | 0 Participants | 1 Participants | 12 Participants |
| ECOG Performance Status 1 | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| ECOG Performance Status 2 | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 1 Participants | 1 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 11 Participants | 0 Participants | 1 Participants | 10 Participants |
| Sex: Female, Male Female | 6 Participants | 0 Participants | 0 Participants | 6 Participants |
| Sex: Female, Male Male | 10 Participants | 1 Participants | 1 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 1 | 0 / 1 |
| other Total, other adverse events | 14 / 14 | 1 / 1 | 1 / 1 |
| serious Total, serious adverse events | 7 / 14 | 0 / 1 | 0 / 1 |
Outcome results
Primary
Objective Response Rate (ORR)
ORR was assessed by the investigator and included complete response (CR), partial response (PR), marrow complete remission (MR), and hematologic improvement (HI) according to the MDS International Working Group (IWG) criteria.
Time frame: 1 year
Population: Full analysis set (FAS) includes subjects enrolled in Protocol Amendment 3 (version 09 Jul 2017) and received at least one dose of tipifarnib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Original Cohort | Objective Response Rate (ORR) | 0 Participants |
| Regimen 1: Tipifarnib | Objective Response Rate (ORR) | 0 Participants |
| Regimen 2: Tipifarnib | Objective Response Rate (ORR) | 0 Participants |
Secondary
Duration of Response
Duration of response is defined as the number of days from the start date of response (whichever response is achieved first) to the first date that progressive disease is objectively documented.
Time frame: 1 year
Population: FAS includes subjects enrolled in Protocol Amendment 3 (version 09 Jul 2017) and received at least one dose of tipifarnib.
Secondary
Duration of Transfusion Independence
Duration of transfusion independence is defined as the period of time where participants achieved transfusion independence.
Time frame: 1 year
Population: FAS includes subjects enrolled in Protocol Amendment 3 (version 09 Jul 2017) and received at least one dose of tipifarnib.
Secondary
Hematologic Improvement
Number of subjects who experienced hematologic improvements (erythroid response, platelet response, or neutrophil response).
Time frame: 1 year
Population: FAS includes subjects enrolled in Protocol Amendment 3 (version 09 Jul 2017) and received at least one dose of tipifarnib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Original Cohort | Hematologic Improvement | 0 Participants |
| Regimen 1: Tipifarnib | Hematologic Improvement | 0 Participants |
| Regimen 2: Tipifarnib | Hematologic Improvement | 1 Participants |
Secondary
Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)
TEAEs are defined as AEs that started on or after the first dose of study drug and within approximately 30 days of the last administration of study drug. AEs were summarized by the number and percentage of subjects who experienced the event, according to system organ class and preferred term. A subject reporting multiple cases of the same AE will be counted once within each system organ class and similarly counted once within each preferred term.
Time frame: 1 year
Population: The All Subjects as Treated (ASaT) population consisted of all enrolled subjects who received at least 1 dose of tipifarnib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Original Cohort | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Subjects with one or more study drug-related serious TEAE | 1 Participants |
| Original Cohort | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Subjects with one or more study drug-related TEAE | 14 Participants |
| Original Cohort | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Subjects with one or more TEAE | 14 Participants |
| Original Cohort | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Subjects with one or more serious TEAE | 7 Participants |
| Regimen 1: Tipifarnib | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Subjects with one or more study drug-related TEAE | 1 Participants |
| Regimen 1: Tipifarnib | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Subjects with one or more serious TEAE | 0 Participants |
| Regimen 1: Tipifarnib | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Subjects with one or more study drug-related serious TEAE | 0 Participants |
| Regimen 1: Tipifarnib | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Subjects with one or more TEAE | 1 Participants |
| Regimen 2: Tipifarnib | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Subjects with one or more study drug-related serious TEAE | 0 Participants |
| Regimen 2: Tipifarnib | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Subjects with one or more serious TEAE | 0 Participants |
| Regimen 2: Tipifarnib | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Subjects with one or more TEAE | 1 Participants |
| Regimen 2: Tipifarnib | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Subjects with one or more study drug-related TEAE | 1 Participants |
Secondary
Overall Survival (OS) at 1 Year
OS is defined as the time (in months) from enrollment to occurrence of death due to any cause within 1 year (approximately 4 time intervals for disease assessments) of either first administration of tipifarnib or the last disease assessment.
Time frame: 1 year
Population: FAS includes subjects enrolled in Protocol Amendment 3 (version 09 Jul 2017) and received at least one dose of tipifarnib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen 1: Tipifarnib | Overall Survival (OS) at 1 Year | 0 Participants |
| Regimen 2: Tipifarnib | Overall Survival (OS) at 1 Year | 0 Participants |
Secondary
Progression-free Survival (PFS) at 1 Year
PFS is defined as the time (in months) from enrollment to either first observation of progressive disease or occurrence of death due to any cause within 1 year (approximately 4 time intervals for disease assessments) of either first administration of tipifarnib or the last disease assessment.
Time frame: 1 year
Population: FAS includes subjects enrolled in Protocol Amendment 3 (version 09 Jul 2017) and received at least one dose of tipifarnib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen 1: Tipifarnib | Progression-free Survival (PFS) at 1 Year | 0 Participants |
| Regimen 2: Tipifarnib | Progression-free Survival (PFS) at 1 Year | 0 Participants |
Secondary
Rate of Transfusion Independence
Rate of transfusion independence is defined as number of participants with transfusion independence at any response assessment over 1 year.
Time frame: 1 year
Population: FAS includes subjects enrolled in Protocol Amendment 3 (version 09 Jul 2017) and received at least one dose of tipifarnib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Original Cohort | Rate of Transfusion Independence | 0 Participants |
| Regimen 1: Tipifarnib | Rate of Transfusion Independence | 0 Participants |
| Regimen 2: Tipifarnib | Rate of Transfusion Independence | 0 Participants |