Relapsed or Refractory Peripheral T-Cell Lymphoma
Conditions
Keywords
PTCL-NOS, Lymphoma, AITL, Nodal T-follicular helper phenotype, ALCL, Hepatosplenic T-cell lymphoma, EATL, Extranodal (NK) T-cell lymphoma, Wild Type CXCL12 3' UTR
Brief summary
Phase II study designed to investigate antitumor activity in terms of objective response rate (ORR) of tipifarnib subjects with advanced Peripheral T-Cell Lymphoma (PTCL). Tipifarnib will be administered orally until disease progression.
Detailed description
This Phase II study will investigate the antitumor activity in terms of ORR of tipifarnib in subjects with relapsed or refractory PTCL. The first 18 subjects may be of the following PTCL sub-types: PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-positive and negative anaplastic large cell lymphoma (ALCL), hepatosplenic T-cell lymphoma, enteropathy-associate T-cell lymphoma (EATL), extranodal natural killer (NK) T-cell lymphoma, nasal type and subcutaneous panniculitis-like T-cell lymphoma. The AITL expansion cohort (N=32) will enroll only subjects with AITL. An additional cohort of patients (N=12) expressing the wild type CXCL12 3' UTR will be enrolled in order to explore the benefits of tipifarnib treatment observed in patients having an absence of this gene variation or single nucleotide variation (SNV). Tumor response assessments will be conducted according to Lugano Classification and/or mSWAT criteria. Tumor assessments will be performed approximately every 8 weeks (cycles 2-6) and at least once approximately every 12 weeks thereafter (Cycles 9, 12, 15, etc.), and will continue until disease progression. Subjects experiencing a complete response may be considered for bone marrow transplantation. Upon disease progression, all subjects will be followed for survival and the use of subsequent therapy. All subjects will be followed for safety during treatment and up to approximately 30 days after treatment discontinuation or until before the initiation of another anti-cancer therapy. Additional follow up may be implemented until the subject recovers from any emergent treatment related toxicity or the adverse event is considered irreversible by the investigator.
Interventions
DRUGTipifarnib
oral
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. Diagnosis of PTCL according to the most recent edition of the World Health Organization (WHO) Classification of Tumors of Hematopoietic or Lymphoid Tissues, as follows: 1. Anaplastic large cell lymphoma (ALCL), ALK positive 2. ALCL, ALK negative 3. Angioimmunoblastic T-cell lymphoma (AITL) 4. Enteropathy-associated T-cell lymphoma 5. Extranodal natural killer (NK) T-cell lymphoma, nasal type 6. Hepatosplenic T-cell lymphoma 7. Peripheral T-cell lymphoma, not otherwise specified (NOS) 8. Subcutaneous panniculitis-like T-cell lymphoma 2. For enrollment into the AITL expansion cohort, subjects must have the diagnosis of AITL, nodal PTCL with T-follicular helper phenotype or follicular PTC. 3. For enrollment into the CXCL12+ PTCL expansion cohort, subjects must have the diagnosis of PTCL (a - h subtypes listed above, except AITL), consent to provide buccal swabs for CXCL12 SNP testing, and be found to be CXCL12+ based on testing by a Sponsor approved methodology. 4. Relapsed or are refractory to at least 1 prior systemic cytotoxic therapy. -Subjects must have received conventional therapy as a prior therapy. 5. Subject has consented to provide at least 6 unstained tumor slides (10 preferred) or an FFPE block for biomarker testing. 6. Subject has measurable disease as determined by the Lugano Classification and/or mSWAT. 7. At least 2 weeks since the last systemic therapy regimen prior to enrollment. 8. At least 2 weeks since last radiotherapy if radiation was localized to the only site of measurable disease, unless there is documentation of disease progression of the irradiated site. Subjects must have recovered from all acute toxicities from radiotherapy. 9. ECOG performance status of 0-2 10. Acceptable liver and renal function 11. Acceptable hematologic status 12. Female subjects must be either: 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 an adequate method of contraception consisting of two-barrier method or one barrier method with a spermicide or intrauterine device. Both females and male subjects with female partners of child- bearing potential must agree to use an adequate 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. 13. Written and voluntary informed consent.
Exclusion criteria
1. Diagnosis of any of the following: 1. Precursor T-cell lymphoma or leukemia 2. Adult T-cell lymphoma/leukemia (ATLL) 3. T-cell prolymphocytic leukemia 4. T-cell large granular lymphocytic leukemia 5. Primary cutaneous type anaplastic large cell lymphoma 6. Mycosis fungoide/Sezary syndrome 2. Ongoing treatment with an anticancer agent not contemplated in this protocol. 3. Prior treatment (at least 1 full treatment cycle) with an FTase inhibitor. 4. Any history of clinically relevant coronary artery disease or myocardial infarction within the last 3 years. 5. Known central nervous system lymphoma. 6. Stem cell transplant less than 3 months prior to enrolment. 7. Non-tolerable \> Grade 2 neuropathy or evidence of unstable neurological symptoms within 4 weeks of Cycle 1 Day 1. 8. Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, without complete recovery. 9. Other active malignancy requiring therapy such as radiation, chemotherapy, or immunotherapy. 10. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy. Known infection with HIV, or an active infection with hepatitis B or hepatitis C. 11. Subjects who have exhibited allergic reactions to tipifarnib, or structural compounds similar to tipifarnib or to its excipients. This includes hypersensitivity to imidazoles, such as clotrimazole, ketoconazole, miconazole and others in this drug class. 12. 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. 13. The subject has legal incapacity or limited legal capacity. 14. Dementia or significantly altered mental status that would limit the understanding or rendering of informed consent and compliance with the requirements of this protocol. 15. 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 approximately 3 years | The ORR (complete response \[CR\] or partial response \[PRs\]) of tipifarnib was based on response assessments according to the Lugano Classification. Two-sided 95% confidence intervals (CIs) were based on either Wilson approximation (N \> 4) or Clopper-Pearson method (N ≤ 4). CR: PET-CT-based response, score of 1-3 on five-point scale (5PS) for lymph nodes and extralymphatic sites, no evidence of fluorodeoxyglucose (FDG)-avid disease in marrow. CT-based response, target nodes and masses regress to 1.5 cm in longest transverse diameter, no extralymphatic sites of disease, normal bone marrow morphology. PR: PET-CT-based response, score of 4-5 on 5PS with reduced uptake compared to baseline for lymph nodes and extralymphatic sites, residual uptake reduced compared to baseline in the bone marrow. CT-based response, ≥ 50% decrease in sum of the product of perpendicular diameters of up to 6 target measurable nodes and extranodal sites, spleen regressed by \> 50% in length beyond normal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to approximately 3 years | PFS was defined as the time (in months) from first dose (Cycle 1 Day 1) to either first observation of progressive disease (PD) or occurrence of death due to any cause within 126 days (approximately 2 time-intervals for tumor assessments) of either first administration of tipifarnib or the last tumor assessment. Observation of PD could have been by either documented radiographic progression (i.e., scan results) or documentation of symptomatic or clinical progression agreed upon and documented by investigators. In subjects without a progression date or with a death date more than 126 days after the first administration of study drugs or the last tumor assessment, the PFS time was censored on the date of last tumor assessment or date of first administration of study tipifarnib. The duration of the PFS was analyzed using the Kaplan-Meier (KM) method. 95% CIs were calculated using Hall-Wellner Method. |
| Duration of Response (DOR) | Up to approximately 3 years | DOR was defined as the time (in months) from the start date of the objective response to the first date of either documented PD or death. No data imputations were conducted for missing data. In the event of a maintained response, the DOR was censored at the last evaluable non-PD assessment. The DOR was analyzed using the KM method. 95% CIs were calculated using Hall-Wellner Method. |
| Number of Subjects That Experienced One or More Treatment-emergent Adverse Events (TEAEs) | Up to approximately 3 years | An adverse event (AE) was any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product, which did not necessarily have a causal relationship with this treatment. TEAEs were defined as AEs that started on or after the first dose of study drug and within 30 days of the last administration of study drug or immediately before the initiation of any other anticancer therapy. The Investigator was required to grade the severity/intensity of each AE according to NCI-CTCAE version 4.03. If a severity/intensity of Grade 4 (life-threatening) or 5 (death) was applied to an AE, then the Investigator also reported the event as a serious AE. |
Countries
South Korea, Spain, United States
Participant flow
Recruitment details
The first subject was enrolled on 25 Feb 2016 (13 in Europe; 52 outside Europe) and the date of the last visit was 31 Mar 2021. Overall, 65 subjects were enrolled into cohorts with angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS), PTCL-NOS whose tumors expressed high levels of C-X-C motif chemokine 12 (CXCL12+), and Other (anaplastic large cell lymphoma-anaplastic lymphoma kinase \[ALCL-ALK negative\] and PTCL-subtype not specified).
Pre-assignment details
Only consented subjects who met all the eligibility criteria were enrolled in the study. All screening evaluations were to be completed within 4 weeks (28 days) of Cycle 1 Day 1. Screen failure reasons were not included in the database.
Participants by arm
| Arm | Count |
|---|---|
| Cohort AITL Subjects with AITL received tipifarnib as monotherapy. Tipifarnib was administered with food at a starting dose of 300 mg orally BID on Days 1 - 21 of 28-day treatment cycles.
In the absence of unmanageable toxicity, treatment may have been continued as long as the investigator considered that the treatment was providing clinical benefit for up to 12 months since the subject's enrollment. Treatment may have continued beyond 12 months upon agreement by the investigator and sponsor if there was documented evidence of sustained clinical benefit. | 38 |
| Cohort PTCL-NOS Subjects with PTCL-NOS (not including subjects with PTCL-NOS CXCL12+) received tipifarnib as monotherapy. Tipifarnib was administered with food at a starting dose of 300 mg orally BID on Days 1 - 21 of 28-day treatment cycles.
In the absence of unmanageable toxicity, treatment may have been continued as long as the investigator considered that the treatment was providing clinical benefit for up to 12 months since the subject's enrollment. Treatment may have continued beyond 12 months upon agreement by the investigator and sponsor if there was documented evidence of sustained clinical benefit. | 14 |
| Cohort PTCL-NOS, CXCL12+ Subjects with PTCL-NOS CXCL12+ (not including subjects with PTCL-NOS) received tipifarnib as monotherapy. Tipifarnib was administered with food at a starting dose of 300 mg orally BID on Days 1 - 21 of 28-day treatment cycles.
In the absence of unmanageable toxicity, treatment may have been continued as long as the investigator considered that the treatment was providing clinical benefit for up to 12 months since the subject's enrollment. Treatment may have continued beyond 12 months upon agreement by the investigator and sponsor if there was documented evidence of sustained clinical benefit. | 11 |
| Cohort Other Subjects with other indications (including ALCL-ALK negative and PTCL-subtype not specified per protocol) received tipifarnib as monotherapy. Tipifarnib was administered with food at a starting dose of 300 mg orally BID on Days 1 - 21 of 28-day treatment cycles.
In the absence of unmanageable toxicity, treatment may have been continued as long as the investigator considered that the treatment was providing clinical benefit for up to 12 months since the subject's enrollment. Treatment may have continued beyond 12 months upon agreement by the investigator and sponsor if there was documented evidence of sustained clinical benefit. | 2 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 9 | 0 | 3 | 0 |
| Overall Study | Disease Progression | 22 | 12 | 5 | 2 |
| Overall Study | Miscellaneous | 1 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 2 | 0 | 1 | 0 |
| Overall Study | Termination for Symptomatic Deterioration | 1 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Cohort Other | Cohort PTCL-NOS, CXCL12+ | Cohort AITL | Cohort PTCL-NOS |
|---|---|---|---|---|---|
| Age, Continuous | 65.32 years STANDARD_DEVIATION 11.6 | 56.68 years STANDARD_DEVIATION 12 | 65.74 years STANDARD_DEVIATION 12.6 | 65.50 years STANDARD_DEVIATION 10.7 | 65.73 years STANDARD_DEVIATION 13.7 |
| Eastern Cooperative Oncology Group (ECOG) Performance Score Performance Score 0 | 26 Participants | 0 Participants | 5 Participants | 18 Participants | 3 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Score Performance Score 1 | 31 Participants | 2 Participants | 6 Participants | 13 Participants | 10 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Score Performance Score 2 | 8 Participants | 0 Participants | 0 Participants | 7 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 61 Participants | 2 Participants | 9 Participants | 36 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 12 Participants | 0 Participants | 0 Participants | 12 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 46 Participants | 1 Participants | 9 Participants | 23 Participants | 13 Participants |
| Sex: Female, Male Female | 24 Participants | 1 Participants | 5 Participants | 16 Participants | 2 Participants |
| Sex: Female, Male Male | 41 Participants | 1 Participants | 6 Participants | 22 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 13 / 38 | 8 / 14 | 4 / 11 | 1 / 2 |
| other Total, other adverse events | 38 / 38 | 14 / 14 | 11 / 11 | 2 / 2 |
| serious Total, serious adverse events | 21 / 38 | 8 / 14 | 8 / 11 | 1 / 2 |
Outcome results
Primary
Objective Response Rate (ORR)
The ORR (complete response \[CR\] or partial response \[PRs\]) of tipifarnib was based on response assessments according to the Lugano Classification. Two-sided 95% confidence intervals (CIs) were based on either Wilson approximation (N \> 4) or Clopper-Pearson method (N ≤ 4). CR: PET-CT-based response, score of 1-3 on five-point scale (5PS) for lymph nodes and extralymphatic sites, no evidence of fluorodeoxyglucose (FDG)-avid disease in marrow. CT-based response, target nodes and masses regress to 1.5 cm in longest transverse diameter, no extralymphatic sites of disease, normal bone marrow morphology. PR: PET-CT-based response, score of 4-5 on 5PS with reduced uptake compared to baseline for lymph nodes and extralymphatic sites, residual uptake reduced compared to baseline in the bone marrow. CT-based response, ≥ 50% decrease in sum of the product of perpendicular diameters of up to 6 target measurable nodes and extranodal sites, spleen regressed by \> 50% in length beyond normal.
Time frame: Up to approximately 3 years
Population: The Full Analysis Set (FAS) Population excluding subjects for the following reasons: no baseline data; failure to receive at least 1 dose of tipifarnib; no post-baseline endpoint data subsequent to at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort AITL | Objective Response Rate (ORR) | 56.3 percentage of participants |
| Cohort PTCL-NOS | Objective Response Rate (ORR) | 7.1 percentage of participants |
| Cohort PTCL-NOS, CXCL12+ | Objective Response Rate (ORR) | 40.0 percentage of participants |
| Cohort Other | Objective Response Rate (ORR) | 0.0 percentage of participants |
Comparison: Null hypothesis H0: PORR = 10% versus HA: PORR \> 10% will be tested at a = 0.05 significance level using a two-sided binomial test. The choice of test statistics was driven by the method used for interval estimation.p-value: 0Wilson approximation
Comparison: Null hypothesis H0: PORR = 10% versus HA: PORR \> 10% will be tested at a = 0.05 significance level using a two-sided binomial test. The choice of test statistics was driven by the method used for interval estimation.p-value: 1Wilson approximation
Comparison: Null hypothesis H0: PORR = 10% versus HA: PORR \> 10% will be tested at a = 0.05 significance level using a two-sided binomial test. The choice of test statistics was driven by the method used for interval estimation.p-value: 0.026Wilson approximation
Comparison: Null hypothesis H0: PORR = 10% versus HA: PORR \> 10% will be tested at a = 0.05 significance level using a two-sided binomial test. The choice of test statistics was driven by the method used for interval estimation.p-value: 1Clopper-Pearson method
Secondary
Duration of Response (DOR)
DOR was defined as the time (in months) from the start date of the objective response to the first date of either documented PD or death. No data imputations were conducted for missing data. In the event of a maintained response, the DOR was censored at the last evaluable non-PD assessment. The DOR was analyzed using the KM method. 95% CIs were calculated using Hall-Wellner Method.
Time frame: Up to approximately 3 years
Population: The FAS Population excluding subjects for the following reasons: no baseline data; failure to receive at least 1 dose of tipifarnib; no post-baseline endpoint data subsequent to at least 1 dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort AITL | Duration of Response (DOR) | 7.8 months |
| Cohort PTCL-NOS | Duration of Response (DOR) | 1.0 months |
| Cohort PTCL-NOS, CXCL12+ | Duration of Response (DOR) | 2.8 months |
Secondary
Number of Subjects That Experienced One or More Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product, which did not necessarily have a causal relationship with this treatment. TEAEs were defined as AEs that started on or after the first dose of study drug and within 30 days of the last administration of study drug or immediately before the initiation of any other anticancer therapy. The Investigator was required to grade the severity/intensity of each AE according to NCI-CTCAE version 4.03. If a severity/intensity of Grade 4 (life-threatening) or 5 (death) was applied to an AE, then the Investigator also reported the event as a serious AE.
Time frame: Up to approximately 3 years
Population: The ASaT population consists of all enrolled subjects who received at least 1 dose of tipifarnib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort AITL | Number of Subjects That Experienced One or More Treatment-emergent Adverse Events (TEAEs) | TEAEs | 38 Participants |
| Cohort AITL | Number of Subjects That Experienced One or More Treatment-emergent Adverse Events (TEAEs) | Serious TEAEs | 21 Participants |
| Cohort PTCL-NOS | Number of Subjects That Experienced One or More Treatment-emergent Adverse Events (TEAEs) | Serious TEAEs | 8 Participants |
| Cohort PTCL-NOS | Number of Subjects That Experienced One or More Treatment-emergent Adverse Events (TEAEs) | TEAEs | 14 Participants |
| Cohort PTCL-NOS, CXCL12+ | Number of Subjects That Experienced One or More Treatment-emergent Adverse Events (TEAEs) | TEAEs | 11 Participants |
| Cohort PTCL-NOS, CXCL12+ | Number of Subjects That Experienced One or More Treatment-emergent Adverse Events (TEAEs) | Serious TEAEs | 8 Participants |
| Cohort Other | Number of Subjects That Experienced One or More Treatment-emergent Adverse Events (TEAEs) | TEAEs | 2 Participants |
| Cohort Other | Number of Subjects That Experienced One or More Treatment-emergent Adverse Events (TEAEs) | Serious TEAEs | 1 Participants |
Secondary
Progression-free Survival (PFS)
PFS was defined as the time (in months) from first dose (Cycle 1 Day 1) to either first observation of progressive disease (PD) or occurrence of death due to any cause within 126 days (approximately 2 time-intervals for tumor assessments) of either first administration of tipifarnib or the last tumor assessment. Observation of PD could have been by either documented radiographic progression (i.e., scan results) or documentation of symptomatic or clinical progression agreed upon and documented by investigators. In subjects without a progression date or with a death date more than 126 days after the first administration of study drugs or the last tumor assessment, the PFS time was censored on the date of last tumor assessment or date of first administration of study tipifarnib. The duration of the PFS was analyzed using the Kaplan-Meier (KM) method. 95% CIs were calculated using Hall-Wellner Method.
Time frame: Up to approximately 3 years
Population: The FAS Population excluding subjects for the following reasons: no Baseline data; failure to receive at least 1 dose of tipifarnib; no post-baseline endpoint data subsequent to at least 1 dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort AITL | Progression-free Survival (PFS) | 3.6 months |
| Cohort PTCL-NOS | Progression-free Survival (PFS) | 2.1 months |
| Cohort PTCL-NOS, CXCL12+ | Progression-free Survival (PFS) | 5.3 months |
| Cohort Other | Progression-free Survival (PFS) | 1.4 months |