Leukemia, Myelomonocytic, Chronic
Conditions
Brief summary
A Phase 2 study to investigate the antitumor activity in terms of overall response rate (ORR) of tipifarnib in approximately 36 eligible subjects with Myelodysplastic/Myeloproliferative Neoplasias (MDS/MPN), including Chronic Myelomonocytic Leukemia (CMML), and 36 eligible subjects with Acute Myeloid Leukemia (AML). Subjects received tipifarnib 1200 mg to be taken orally with food, twice daily, for 7 days in alternating weeks (Days 1 to 7 and Days 15 to 21) in 28-day cycles. Following amendment 3 subjects (Cohorts 1-4) will receive tipifarnib administered at a dose of 400 mg, orally with food, twice a day (bid) for 21 days in 28-day cycles.
Detailed description
This Phase 2 study will investigate the antitumor activity in terms of ORR of tipifarnib in subjects with Myelodysplastic/Myeloproliferative Neoplasias (MDS/MPN cohorts) and Acute Myeloid Leukemia (AML cohorts). For MDS/MPN cohorts, this study will assess the antitumor activity of tipifarnib, in terms of ORR, in subjects with MDS/MPN, including CMML, who have a high ratio of expression of CXCR4 to CXCR2 (CXCR4/2 ratio) in their bone marrow and in those with a low CXCR4/2 ratio. For AML cohorts, this study will assess the antitumor activity of tipifarnib, in terms of ORR, in subjects with AML who have a high ratio of expression of CXCR4 to CXCR2 (CXCR4/2 ratio) in their bone marrow and in those with low CXCR4/2 ratio. Subjects enrolled in the study will consist of patients with KRAS, NRAS wild type status. 1. Subjects with MDS/MPN with high CXCR4/2 ratio 2. Subjects with MDS/MPN with low CXCR4/2 ratio 3. Subjects with AML with high CXCR4/2 ratio 4. Subjects with AML with low CXCR4/2 ratio
Interventions
DRUGTipifarnib
Oral tablet
Sponsors
Kura Oncology, Inc.
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
1. Subject is at least 18 years of age. 2. For subjects to be enrolled in the CMML or MDS/MPN cohorts: a. Diagnosis of CMML or MDS/MPN as defined by the World Health Organization (WHO) criteria (2008). 3. For subjects enrolled in the AML cohort: 1. Documented pathological evidence of AML, as defined by WHO criteria (2008) 2. Refractory to previous induction chemotherapy, relapsed disease, or age ≥ 60 and not appropriate for standard cytotoxic therapy due to age, performance status, and/or adverse risk factors according to the treating physician 4. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2. 5. Subject is willing and able to comply with scheduled visits, treatment plans, laboratory tests and other procedures (including bone marrow assessments). 6. At least 1 week since the last systemic therapy regimen prior to Cycle 1 Day 1. Subjects on a stable dose of hydroxyurea for at least 2 weeks prior to Cycle 1 Day 1 may continue on hydroxyurea until Cycle 1 Day 14. 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. 7. Acceptable liver function: 1. Total bilirubin ≤ upper limit of normal (ULN). 2. AST (SGOT) and ALT (SGPT) ≤ 1.5 x ULN. 8. 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. 9. 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 28 days after last dose of trial medication for females and 90 days for males. Female subjects must have a negative serum or urine pregnancy test within 72 hours prior to start of trial medication. 3. And, not breast feeding at any time during the study. 10. Written and voluntary informed consent understood, signed and dated.
Exclusion criteria
1. Neoplasia harbours RAS mutation (NRAS mutant, KRAS mutant or double mutant) 2. Acute promyelocytic leukemia or Bcr-Abl positive leukemia (chronic myelogenous leukemia in blast crisis) 3. Clinically active CNS leukemia 4. CMML with t(5;12) that have not yet received imatinib. 5. Participation in any interventional study within 1 week of randomization or 5 half-lives of the prior treatment agent (whichever is longer). 6. Ongoing treatment with an anticancer agent for CMML, MDS/MPN or AML not contemplated in this protocol. Subjects on a stable dose of hydroxyurea for at least 2 weeks prior to Cycle 1 Day 1 may continue on hydroxyurea until Cycle 1 Day 14. 7. Hematopoietic stem cell transplantation (HSCT) performed within 3 months prior to Cycle 1 Day 1. 8. Concurrent use of granulocyte macrophage colony-stimulating factor (GM-CSF). 9. Prior treatment (at least 1 full treatment cycle) with a farnesyltransferase inhibitor. 10. 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. 11. Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, without complete recovery. 12. 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). 13. Active and 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. 14. 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. 15. The subject has legal incapacity or limited legal capacity. 16. 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) | Up to 12 months | The ORR was estimated based on the number of participants who achieved an objective response (OR) (complete response \[CR\], complete cytogenetic remission \[CCR\], partial remission \[PR\], marrow response \[MR\], or clinical benefit \[CB\] performed by Principal Investigator according to the MDS/MPN International Working Group \[IWG\] criteria). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DoR) | Up to approximately 15 months | DoR was measured from the date the participant first met the criteria of an OR to the date that the participant progressed or until death from any cause during the period of disease assessments. Participants without progression or death were censored at the date of the last disease assessment. Participants who received subsequent anticancer therapy were censored at the date of last disease assessment before subsequent anticancer therapy. The median duration of response and corresponding 95% CI was estimated using the Kaplan Meier method. |
| Progression Free Survival (PFS) | 1 year | The PFS time was defined as the time from the date of consent signed to the date of documented disease progression or death due to any cause, whichever occurred first. Participants without progression or death were censored at the date of the last disease assessment. Participants who received subsequent anticancer therapy were censored at the date of the last disease assessment before subsequent anticancer therapy. The Kaplan-Meier product-limit method was used to estimate the 1-year PFS rate, as well as the corresponding 95% CI. |
| Overall Survival (OS) | Up to approximately 15 months | OS time was defined as the time from the date of consent signed to the date of death due to any cause. Participants who were alive or lost to follow-up by the end of the study were censored at the date last known to be alive. The Kaplan-Meier method was used to estimate the proportion (%) of subjects without an event at 12 months, as well as their corresponding 95% CI. |
| Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Up to approximately 3 years | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, which does not necessarily have a causal relationship with it. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AE severity was rated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03.: grade 1(mild), grade 2(moderate), grade 3(severe), grade 4(life-threatening), grade 5(death). An AE was considered serious if resulted in any of the following: death, life-threatening, caused inpatient hospitalization or prolonged it, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital abnormality/birth defect, or was an important medical event. |
Countries
United States
Participant flow
Recruitment details
Participants affected by chronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS)/myeloproliferative neoplasms (MPN) were recruited across 10 sites in the United States between January 2017 and November 2020.
Pre-assignment details
Participants w/ CMML were grouped by KRAS/NRAS status (wild type \[WT\], mutation \[Mut\], missing) & received tipifarnib 1200mg twice daily (BID) for 7 days, alternating weeks (Days 1-7, 15-21) in 28-day cycles. Following PA3 participants received tipifarnib 400mg orally w/ food, BID for 21 days in 28-day cycles. Those w/ MDS/MPN were stratified by ratio of expression (high/low) between CXCR4 & CXCR2 (CXCR4/2 ratio) receptors to receive tipifarnib 400mg orally, BID on Day 1-21 of each 28-day cycle.
Participants by arm
| Arm | Count |
|---|---|
| KRAS/NRAS WT Participants with CMML received tipifarnib at a starting dose of 1200 mg, BID, for 7 days in alternating weeks (Days 1 to 7 and Days 15 to 21) in 28-day cycles. | 23 |
| KRAS/NRAS Mut Participants with CMML received tipifarnib at a starting dose of 1200 mg, BID, for 7 days in alternating weeks (Days 1 to 7 and Days 15 to 21) in 28-day cycles. | 12 |
| KRAS/NRAS Missing Participants with CMML received tipifarnib at a starting dose of 1200 mg, BID, for 7 days in alternating weeks (Days 1 to 7 and Days 15 to 21) in 28-day cycles. | 2 |
| CXCR4/2 High Participants with MDS/MPN received tipifarnib at a starting dose of 400 mg, orally, BID on Day 1 through 21 of each 28-day treatment cycle. | 3 |
| CXCR4/2 Low Participants with MDS/MPN received tipifarnib at a starting dose of 400 mg, orally, BID on Day 1 through 21 of each 28-day treatment cycle. | 4 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 9 | 5 | 2 | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Other | 1 | 0 | 0 | 0 | 1 |
| Overall Study | Permanent Withdrawal of Consent | 8 | 2 | 0 | 2 | 1 |
| Overall Study | Protocol-defined Disease Progression | 0 | 1 | 0 | 0 | 1 |
| Overall Study | Study Terminated by Sponsor | 1 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | KRAS/NRAS WT | KRAS/NRAS Mut | KRAS/NRAS Missing | CXCR4/2 High | CXCR4/2 Low | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 70.0 years STANDARD_DEVIATION 6.62 | 69.7 years STANDARD_DEVIATION 6.68 | 76.0 years STANDARD_DEVIATION 2.83 | 67.3 years STANDARD_DEVIATION 2.89 | 70.5 years STANDARD_DEVIATION 4.04 | 70.1 years STANDARD_DEVIATION 6.14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 12 Participants | 2 Participants | 3 Participants | 3 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized American Indian/Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian/other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 20 Participants | 10 Participants | 1 Participants | 3 Participants | 4 Participants | 38 Participants |
| Sex: Female, Male Female | 11 Participants | 3 Participants | 1 Participants | 2 Participants | 2 Participants | 19 Participants |
| Sex: Female, Male Male | 12 Participants | 9 Participants | 1 Participants | 1 Participants | 2 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 17 / 37 | 1 / 7 |
| other Total, other adverse events | 37 / 37 | 7 / 7 |
| serious Total, serious adverse events | 23 / 37 | 1 / 7 |
Outcome results
Primary
Objective Response Rate (ORR)
The ORR was estimated based on the number of participants who achieved an objective response (OR) (complete response \[CR\], complete cytogenetic remission \[CCR\], partial remission \[PR\], marrow response \[MR\], or clinical benefit \[CB\] performed by Principal Investigator according to the MDS/MPN International Working Group \[IWG\] criteria).
Time frame: Up to 12 months
Population: Per Protocol Analysis Set (PP Analysis Set): Included participants who received at least 1 dose of tipifarnib and had a baseline disease assessment and at least 1 postbaseline disease assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| KRAS/NRAS WT | Objective Response Rate (ORR) | CB | 1 Participants |
| KRAS/NRAS WT | Objective Response Rate (ORR) | PR | 0 Participants |
| KRAS/NRAS WT | Objective Response Rate (ORR) | CR | 0 Participants |
| KRAS/NRAS WT | Objective Response Rate (ORR) | ORR | 3 Participants |
| KRAS/NRAS WT | Objective Response Rate (ORR) | CCR | 0 Participants |
| KRAS/NRAS WT | Objective Response Rate (ORR) | MR | 2 Participants |
| KRAS/NRAS Mut | Objective Response Rate (ORR) | CCR | 1 Participants |
| KRAS/NRAS Mut | Objective Response Rate (ORR) | CB | 1 Participants |
| KRAS/NRAS Mut | Objective Response Rate (ORR) | PR | 0 Participants |
| KRAS/NRAS Mut | Objective Response Rate (ORR) | ORR | 3 Participants |
| KRAS/NRAS Mut | Objective Response Rate (ORR) | CR | 0 Participants |
| KRAS/NRAS Mut | Objective Response Rate (ORR) | MR | 1 Participants |
| KRAS/NRAS Missing | Objective Response Rate (ORR) | PR | 0 Participants |
| KRAS/NRAS Missing | Objective Response Rate (ORR) | CR | 0 Participants |
| KRAS/NRAS Missing | Objective Response Rate (ORR) | CCR | 0 Participants |
| KRAS/NRAS Missing | Objective Response Rate (ORR) | ORR | 1 Participants |
| KRAS/NRAS Missing | Objective Response Rate (ORR) | MR | 0 Participants |
| KRAS/NRAS Missing | Objective Response Rate (ORR) | CB | 1 Participants |
| CXCR4/2 High | Objective Response Rate (ORR) | ORR | 0 Participants |
| CXCR4/2 High | Objective Response Rate (ORR) | CB | 0 Participants |
| CXCR4/2 High | Objective Response Rate (ORR) | CCR | 0 Participants |
| CXCR4/2 High | Objective Response Rate (ORR) | CR | 0 Participants |
| CXCR4/2 High | Objective Response Rate (ORR) | PR | 0 Participants |
| CXCR4/2 High | Objective Response Rate (ORR) | MR | 0 Participants |
| CXCR4/2 Low | Objective Response Rate (ORR) | PR | 1 Participants |
| CXCR4/2 Low | Objective Response Rate (ORR) | ORR | 1 Participants |
| CXCR4/2 Low | Objective Response Rate (ORR) | MR | 0 Participants |
| CXCR4/2 Low | Objective Response Rate (ORR) | CR | 0 Participants |
| CXCR4/2 Low | Objective Response Rate (ORR) | CB | 0 Participants |
| CXCR4/2 Low | Objective Response Rate (ORR) | CCR | 0 Participants |
Secondary
Duration of Response (DoR)
DoR was measured from the date the participant first met the criteria of an OR to the date that the participant progressed or until death from any cause during the period of disease assessments. Participants without progression or death were censored at the date of the last disease assessment. Participants who received subsequent anticancer therapy were censored at the date of last disease assessment before subsequent anticancer therapy. The median duration of response and corresponding 95% CI was estimated using the Kaplan Meier method.
Time frame: Up to approximately 15 months
Population: PP Analysis Set: Included participants who received at least 1 dose of tipifarnib and had a baseline disease assessment and at least 1 postbaseline disease assessment. Only participants who met the criteria for an OR and progressed or died were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| KRAS/NRAS WT | Duration of Response (DoR) | 14.6 months |
| KRAS/NRAS Mut | Duration of Response (DoR) | NA months |
| KRAS/NRAS Missing | Duration of Response (DoR) | 4.7 months |
| CXCR4/2 Low | Duration of Response (DoR) | NA months |
Secondary
Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, which does not necessarily have a causal relationship with it. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AE severity was rated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03.: grade 1(mild), grade 2(moderate), grade 3(severe), grade 4(life-threatening), grade 5(death). An AE was considered serious if resulted in any of the following: death, life-threatening, caused inpatient hospitalization or prolonged it, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital abnormality/birth defect, or was an important medical event.
Time frame: Up to approximately 3 years
Population: FAS: All enrolled participants who received at least one dose of tipifarnib. Data was pooled into CMML and MDS/MPN arms as pre-specified in statistical analysis plan (SAP).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| KRAS/NRAS WT | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 37 Participants |
| KRAS/NRAS WT | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any tipifarnib-related TEAE | 37 Participants |
| KRAS/NRAS WT | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any serious TEAE | 23 Participants |
| KRAS/NRAS WT | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any tipifarnib-related serious TEAE | 13 Participants |
| KRAS/NRAS Mut | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any tipifarnib-related serious TEAE | 1 Participants |
| KRAS/NRAS Mut | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 7 Participants |
| KRAS/NRAS Mut | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any serious TEAE | 1 Participants |
| KRAS/NRAS Mut | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any tipifarnib-related TEAE | 6 Participants |
Secondary
Overall Survival (OS)
OS time was defined as the time from the date of consent signed to the date of death due to any cause. Participants who were alive or lost to follow-up by the end of the study were censored at the date last known to be alive. The Kaplan-Meier method was used to estimate the proportion (%) of subjects without an event at 12 months, as well as their corresponding 95% CI.
Time frame: Up to approximately 15 months
Population: PP Analysis Set: Included participants who received at least 1 dose of tipifarnib and had a baseline disease assessment and at least 1 post-baseline disease assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| KRAS/NRAS WT | Overall Survival (OS) | 14.4 months |
| KRAS/NRAS Mut | Overall Survival (OS) | NA months |
| KRAS/NRAS Missing | Overall Survival (OS) | 10.6 months |
| CXCR4/2 High | Overall Survival (OS) | NA months |
| CXCR4/2 Low | Overall Survival (OS) | NA months |
Secondary
Progression Free Survival (PFS)
The PFS time was defined as the time from the date of consent signed to the date of documented disease progression or death due to any cause, whichever occurred first. Participants without progression or death were censored at the date of the last disease assessment. Participants who received subsequent anticancer therapy were censored at the date of the last disease assessment before subsequent anticancer therapy. The Kaplan-Meier product-limit method was used to estimate the 1-year PFS rate, as well as the corresponding 95% CI.
Time frame: 1 year
Population: PP Analysis Set: Included participants who received at least 1 dose of tipifarnib and had a baseline disease assessment and at least 1 post-baseline disease assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| KRAS/NRAS WT | Progression Free Survival (PFS) | 9.2 months |
| KRAS/NRAS Mut | Progression Free Survival (PFS) | 4.1 months |
| KRAS/NRAS Missing | Progression Free Survival (PFS) | 10.0 months |
| CXCR4/2 High | Progression Free Survival (PFS) | NA months |
| CXCR4/2 Low | Progression Free Survival (PFS) | 11.0 months |