Teratoma
Conditions
Keywords
Teratoma,, Germ Cell tumor,, incurable teratoma,, CDK4/6,, LEE011
Brief summary
This was a multi-center, randomized, double blind (investigator and subject), placebo controlled Phase II study to determine the efficacy and safety of treatment with ribociclib versus placebo in subjects with progressive relapsed, refractory incurable teratoma. Eligible subjects were randomized in a 2:1 ratio to ribociclib or placebo. After discontinuation of study treatment, patients were followed up for safety, disease progression and overall survival.
Detailed description
Safety follow-up: After discontinuation of study treatment, all subjects were followed for safety for 30 days except in the case of death, loss to follow up, withdrawal of consent, or discontinuation of study treatment to enroll in the ribociclib rollover clinical trial (CLEE011X2X01B). Disease progression follow-up: Subjects who discontinued study drug for any reasons other than disease progression were followed for efficacy every 8 weeks during the first 12 months. After 12 months, they were followed for every 12 weeks until disease progression, death, discontinuation from the study for any other reason (i.e. loss to follow-up or withdrawal of consent), the initiation of a new antineoplastic treatment, or until all subjects had been followed for at least 18 months after their first dose of study drug, or early study termination, whichever occurred first. Survival follow-up: All subjects were followed for survival via a phone call (or during a clinic visit) every 12 weeks and up to one additional time per quarter if a survival update was required to meet safety or regulatory needs. The safety follow-up was carried out until any of the following occurred (whichever occurred first): death, withdrawal of consent, loss to follow-up, at least 18 months had elapsed from when the last subject had started treatment, or when 80% of subjects had died or were lost to follow-up, or early study termination.
Interventions
DRUGLEE011
DRUGLEE011 Placebo
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Diagnosis of teratoma for which no additional standard surgical or medical therapy exists * Patients must have completed at least 1 prior line of chemotherapy for germ cell tumor (except patients who present with primary pure teratoma who need not have received any previous chemotherapy) * Radiographic progression, defined by RECIST v.1.1, after the last cancer treatment and within 12 weeks prior to enrollment, compared with scans within 1 year of enrollment. * Availability of an archival or newly obtained tumor sample (collected at diagnosis or progression) with accompanying pathology report * Meaurable or evaluable extra-cranial disease as defined by RECIST v 1.1 Key
Exclusion criteria
* Malignant germ cell tumors with mixed histology such as embryonal carcinoma, choriocarcinoma, yolk sac tumor or seminoma. Note - this refers to the histology at the time of enrollment, not the histolgy at the time of initial presentation. * Pathologic evidence of malignant transformation * CNS disease unless radiation therapy and/or surgery has been completed and serial evaluation demonstrates stable disease * Prior treatment with any CDK4/6 inhibitor therapy * Systemic antineoplastic therapy or any experimental therapy within 3 weeks before the first dose of study drug (6 weeks for prior nitrosoureas, bevacizumab, or mitomycin C) * Major surgery ≤ 2 weeks or radiotherapy ≤ 4 weeks prior to planned start of study drug or patient has not recovered from major side effects. * Requirement for treatment with any of the prohibited medications including strong CYP3A inhibitors, strong CYP3A inducers, CYP3A substrates with a narrow therapeutic index, and medications with strong risk of QT prolongation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | At 24 months | Date of randomization to the date of the first documented progression or death due to any causeas per RECIST v1.1 (by local investigator assessment). Only includes data prior to cross over. Disease progression follow-up: Subjects who discontinued study drug for any reasons other than disease progression were followed for efficacy every 8 weeks during the first 12 months. After 12 months, they were followed for every 12 weeks until disease progression, death, discontinuation from the study for any other reason (i.e. loss to follow-up or withdrawal of consent), the initiation of a new antineoplastic treatment, or until all subjects had been followed for at least 18 months after their first dose of study drug, or early study termination, whichever occurred first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response (BOR) | At 24 months | as per RECIST v1.1. Only includes data prior to cross over. Placebo arm : the subject who experienced SD as best overall response entered the secondary phase and was treated with LEE011 after he experienced progressive disease, following his best Stable Disease response. In this outcome measure 2, only the best overall response is indicated. |
| Overall Response Rate | At 27 months | Overall response rate (ORR) = complete response (CR) or partial response (PR). ORR was zero, as there were no CRs or PRs in either of the groups |
| Disease Control Rate (DCR) | At 24 months | as per RECIST v1.1. Only includes data prior to cross over. Placebo arm : the disease control rate is based on the best overall response described in the outcome measure 2. |
| Overall Survival (OS) | At 27 months | Only includes data prior to cross over. OS defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died by the date of analysis cut off, OS was censored at the date of last known date patient alive |
| Overall Survival Rate | 1, 2, 3, 6, 9, 12, 15, 18, 21, 24 and 27 months | as per RECIST v1.1. Only includes data prior to cross over. Kaplan-Meier estimates (%) OS rate \[95% CI\] at different timepoints. The overall survival rate at 27 month is 72.9% by Kaplan-Meyer (K-M) estimator; the reason that it is not 75% (1-25%) (Overall survival) is because of censoring. When the other 6 patients were censored would impact the survival rate with K-M method as the number of patients at risk after each censor was changed. NA for the 95% CI is indicated when no patient died at the time of assessment, as the CI could not be calculated as per definition. Results are presented as a % calculated on the total number of participants. |
Countries
France, Netherlands, Spain, United States
Participant flow
Recruitment details
Subjects were randomly assigned to Ribociclib or Placebo in a 2:1 ratio. The 2 subjects from the placebo group (primary phase) entered the secondary treatment phase (cross over) after they experienced disease progression, and were then treated with LEE01. One patient from the LEE arm entered the secondary treatment phase.
Pre-assignment details
42 subjects were planned to be included (28 for the LEE011 arm and 14 for the Placebo arm). The study was stopped prematurely with 10 patients randomized and treated in this study (8 in the ribociclib arm, 2 in the placebo arm).
Participants by arm
| Arm | Count |
|---|---|
| LEE011 600 mg daily dosing days 1-21 of a 28 day cycle | 8 |
| Placebo Arm 600 mg daily dosing days 1-21 of a 28 day cycle | 2 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Primary Phase : Prior to Cross-over | Physician Decision | 2 | 0 |
| Primary Phase : Prior to Cross-over | progressive disease | 3 | 2 |
| Primary Phase : Prior to Cross-over | Withdrawal by Subject | 1 | 0 |
| Secondary Phase : Cross-over to LEE011 | Adverse Event | 0 | 1 |
| Secondary Phase : Cross-over to LEE011 | Lack of Efficacy | 1 | 0 |
Baseline characteristics
| Characteristic | LEE011 | Placebo Arm | Total |
|---|---|---|---|
| Age, Continuous | 32.3 years STANDARD_DEVIATION 6.76 | 40.5 years STANDARD_DEVIATION 17.68 | 33.9 years STANDARD_DEVIATION 9.07 |
| Race/Ethnicity, Customized Caucasian | 4 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Native American | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 3 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 8 Participants | 2 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 2 | 0 / 10 |
| other Total, other adverse events | 8 / 8 | 1 / 2 | 9 / 10 |
| serious Total, serious adverse events | 3 / 8 | 0 / 2 | 3 / 10 |
Outcome results
Primary
Progression Free Survival (PFS)
Date of randomization to the date of the first documented progression or death due to any causeas per RECIST v1.1 (by local investigator assessment). Only includes data prior to cross over. Disease progression follow-up: Subjects who discontinued study drug for any reasons other than disease progression were followed for efficacy every 8 weeks during the first 12 months. After 12 months, they were followed for every 12 weeks until disease progression, death, discontinuation from the study for any other reason (i.e. loss to follow-up or withdrawal of consent), the initiation of a new antineoplastic treatment, or until all subjects had been followed for at least 18 months after their first dose of study drug, or early study termination, whichever occurred first.
Time frame: At 24 months
Population: Full analysis set. After 10 subjects were enrolled and treated, the recruitment was halted due to business reasons.There were no safety concerns which contributed to the decision to halt enrollment. Limited efficacy analyses were performed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LEE011 | Progression Free Survival (PFS) | 71.4 Days |
| Placebo Arm | Progression Free Survival (PFS) | 0.0 Days |
Secondary
Best Overall Response (BOR)
as per RECIST v1.1. Only includes data prior to cross over. Placebo arm : the subject who experienced SD as best overall response entered the secondary phase and was treated with LEE011 after he experienced progressive disease, following his best Stable Disease response. In this outcome measure 2, only the best overall response is indicated.
Time frame: At 24 months
Population: Full analysis set. After 10 subjects were enrolled and treated, the recruitment was halted due to business reasons.There were no safety concerns which contributed to the decision to halt enrollment. Limited efficacy analyses were performed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LEE011 | Best Overall Response (BOR) | Stable Disease (SD) | 8 Participants |
| LEE011 | Best Overall Response (BOR) | Progressive Disease (PD) | 0 Participants |
| Placebo Arm | Best Overall Response (BOR) | Stable Disease (SD) | 1 Participants |
| Placebo Arm | Best Overall Response (BOR) | Progressive Disease (PD) | 1 Participants |
Secondary
Disease Control Rate (DCR)
as per RECIST v1.1. Only includes data prior to cross over. Placebo arm : the disease control rate is based on the best overall response described in the outcome measure 2.
Time frame: At 24 months
Population: Full analysis set. After 10 subjects were enrolled and treated, the recruitment was halted due to business reasons.There were no safety concerns which contributed to the decision to halt enrollment. Limited efficacy analyses were performed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LEE011 | Disease Control Rate (DCR) | 100 percentage of participants |
| Placebo Arm | Disease Control Rate (DCR) | 50 percentage of participants |
Secondary
Overall Response Rate
Overall response rate (ORR) = complete response (CR) or partial response (PR). ORR was zero, as there were no CRs or PRs in either of the groups
Time frame: At 27 months
Population: Full analysis set. After 10 subjects were enrolled and treated, the recruitment was halted due to business reasons.There were no safety concerns which contributed to the decision to halt enrollment. Limited efficacy analyses were performed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LEE011 | Overall Response Rate | 0 percentage of participants |
| Placebo Arm | Overall Response Rate | 0 percentage of participants |
Secondary
Overall Survival (OS)
Only includes data prior to cross over. OS defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died by the date of analysis cut off, OS was censored at the date of last known date patient alive
Time frame: At 27 months
Population: Full analysis set. After 10 subjects were enrolled and treated, the recruitment was halted due to business reasons.There were no safety concerns which contributed to the decision to halt enrollment. Limited efficacy analyses were performed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LEE011 | Overall Survival (OS) | 6 Participants |
| Placebo Arm | Overall Survival (OS) | 1 Participants |
Secondary
Overall Survival Rate
as per RECIST v1.1. Only includes data prior to cross over. Kaplan-Meier estimates (%) OS rate \[95% CI\] at different timepoints. The overall survival rate at 27 month is 72.9% by Kaplan-Meyer (K-M) estimator; the reason that it is not 75% (1-25%) (Overall survival) is because of censoring. When the other 6 patients were censored would impact the survival rate with K-M method as the number of patients at risk after each censor was changed. NA for the 95% CI is indicated when no patient died at the time of assessment, as the CI could not be calculated as per definition. Results are presented as a % calculated on the total number of participants.
Time frame: 1, 2, 3, 6, 9, 12, 15, 18, 21, 24 and 27 months
Population: Full analysis set.After 10 subjects were enrolled and treated, the recruitment was halted due to business reasons.There were no safety concerns which contributed to the decision to halt enrollment. Limited efficacy analyses were performed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LEE011 | Overall Survival Rate | 6 months | 100 Percentage of Participants |
| LEE011 | Overall Survival Rate | 15 months | 87.5 Percentage of Participants |
| LEE011 | Overall Survival Rate | 3 months | 100 Percentage of Participants |
| LEE011 | Overall Survival Rate | 18 months | 87.5 Percentage of Participants |
| LEE011 | Overall Survival Rate | 9 months | 100 Percentage of Participants |
| LEE011 | Overall Survival Rate | 21 months | 87.5 Percentage of Participants |
| LEE011 | Overall Survival Rate | 2 months | 100 Percentage of Participants |
| LEE011 | Overall Survival Rate | 24 months | 87.5 Percentage of Participants |
| LEE011 | Overall Survival Rate | 12 months | 87.5 Percentage of Participants |
| LEE011 | Overall Survival Rate | 27 months | 72.9 Percentage of Participants |
| LEE011 | Overall Survival Rate | 1 month | 100 Percentage of Participants |
| Placebo Arm | Overall Survival Rate | 27 months | 50.0 Percentage of Participants |
| Placebo Arm | Overall Survival Rate | 1 month | 100 Percentage of Participants |
| Placebo Arm | Overall Survival Rate | 2 months | 100 Percentage of Participants |
| Placebo Arm | Overall Survival Rate | 3 months | 100 Percentage of Participants |
| Placebo Arm | Overall Survival Rate | 6 months | 100 Percentage of Participants |
| Placebo Arm | Overall Survival Rate | 9 months | 100 Percentage of Participants |
| Placebo Arm | Overall Survival Rate | 12 months | 100 Percentage of Participants |
| Placebo Arm | Overall Survival Rate | 15 months | 100 Percentage of Participants |
| Placebo Arm | Overall Survival Rate | 18 months | 100 Percentage of Participants |
| Placebo Arm | Overall Survival Rate | 21 months | 50.0 Percentage of Participants |
| Placebo Arm | Overall Survival Rate | 24 months | 50.0 Percentage of Participants |
Post Hoc
All Collected Deaths
On treatment deaths are collected from first patient first visit up to 30 days after study treatment discontinuation (approximately 12 months, median duration of exposure). Patients with cancer are also followed up for overall survival until the end of the trial. During overall survival (up to 27 months after the first patient first visit), additional deaths were recorded, including deaths due to the cancer disease (having occurred more than 30 days after study drug discontinuation)
Time frame: 12 months, 27 months
Population: Full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LEE011 | All Collected Deaths | Total deaths | 2 Participants |
| LEE011 | All Collected Deaths | Deaths on treatment | 0 Participants |
| LEE011 | All Collected Deaths | Deaths post treatment survival follow up | 2 Participants |
| Placebo Arm | All Collected Deaths | Total deaths | 1 Participants |
| Placebo Arm | All Collected Deaths | Deaths on treatment | 0 Participants |
| Placebo Arm | All Collected Deaths | Deaths post treatment survival follow up | 1 Participants |