Tumors With CDK4/6 Pathway Activation
Conditions
Keywords
Solid malignancy, Hematologic malignancy, Mutations, Amplifications, Signature, CDK4, CDK6, CDK4/6, Cyclin D1, CCND,, Cyclin D3, p16 mutation, CDKN2A, LEE011, Breast cancer, Ovarian cancer, Lymphoma, Mesothelioma, Pancreatic neuroendocrine, Leukemia, Tumor
Brief summary
The purpose of this signal seeking study was to determine whether treatment with LEE011 demonstrates sufficient efficacy in CDK4/6 pathway activated solid tumors and/or hematologic malignancies to warrant further study.
Interventions
DRUGLEE011
Study drug was provided in 200 mg and 50 mg hard gelatin capsules to be taken orally
Sponsors
Novartis Pharmaceuticals
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
* Patient had a confirmed diagnosis of a select solid tumor (except breast cancer (however, triple negative was included), liposarcoma, CRPC, melanoma and teratoma) or hematological malignancy (except mantle cell lymphoma). * Patient must have been pre-identified as having a tumor with CDK4 amplification or mutation, CDK6 amplification or mutation, Cyclin D1 (CCND1) amplification, Cyclin D3 (CCND3) amplification, or p16 (CDKN2A) mutation * Patient had received at least one prior treatment for recurrent, metastatic and /or locally advanced disease and for whom no standard therapy options are anticipated to result in a durable remission. * Patient had progressive and measurable disease as per RECIST 1.1. or other appropriate hematological guidelines. * Patient had an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
Exclusion criteria
* Patients had received prior treatment with LEE011. * Patient had clinically significant resting bradycardia (heart rate \< 50 at rest), tachycardia (heart rate \> 90 at rest), PR interval \> 220 msec, QRS interval \> 109 msec, or QTcF \> 450 msec. * Patients had primary CNS tumor or CNS tumor involvement * Patient had received chemotherapy or anticancer therapy ≤ 4 weeks prior to starting study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Solid Tumor Response ≥ 16 Weeks for Based Upon Local Investigator Assessments | Baseline up ≥16 weeks up to approximately 36 months | Clinical benefit (CB) for patients with solid tumors were assessed using RECIST 1.1 and included responses of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) for ≥ 16 weeks. CR and PR (for solid tumors) required a confirmation at least 4 weeks after the initial response observation. For hematologic tumors other appropriate hematological response criteria was applied. CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to \<10 mm, PR=At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study, PD=At least a 20% increase in the sum of diameter of all measured target lesions and also demonstrate an absolute increase of at least 5 mm. FAS |
| Clinical Benefit Rate (CBR) of ≥ 16 Weeks FAS | Baseline and ≥ 16 weeks up to approximately 36 months | CBR was determined by local, Investigator assessment for each tumor assessment and defined as responses of CR + PR + SD for ≥ 16 weeks. CR and PR (for solid tumors) required a confirmation at least 4 weeks after the initial response observation. For hematologic tumors other appropriate hematological response criteria was applied. CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to \<10 mm, PR=At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study, PD=At least a 20% increase in the sum of diameter of all measured target lesions and also demonstrate an absolute increase of at least 5 mm FAS |
| Overall Response Rate (ORR) ≥ 16 Weeks. FAS | Baseline and ≥ 16 weeks up to approximately 36 months | ORR was determined by local, Investigator assessment for each tumor assessment and defined as responses of CR+PR ≥ 16 weeks. FAS |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Baseline up to approximately 36 months | Number of participants Overall survival (OS) is defined as the time from the date of first dose to the date of death due to any cause. |
| Number of Days for Duration of Response for Responders | Baseline up to approximately 36 months | Duration of response (DOR) is defined as time from the first documented response to the date first documented disease progression or relapse or death due to any cause. For patients with solid tumors the assessment criteria will be RECIST 1.1 and will include responses of CR and/or PR. |
| Progression Free Survival (PFS) | Every 8 weeks until death, assessed up to 24 months | Progression-free survival (PFS) is the time from the date of start of treatment to the date of event defined as the first documented progression or death due to any cause within 30 days of the last dose. If a subject has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Progressive disease is defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (Note: the appearance of one or more new lesions is also considered progression) |
Countries
United States
Participant flow
Pre-assignment details
There were 176 patients screened
Participants by arm
| Arm | Count |
|---|---|
| Ribociclib 600 mg LEE011 600 mg (hard gelatin capsules) was administered orally once daily for 3 weeks on/1 week off. A complete treatment cycle was defined as 28 days. | 106 |
| Total | 106 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 8 |
| Overall Study | Death | 3 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Progressive disease | 80 |
| Overall Study | Protocol Violation | 3 |
| Overall Study | Study terminated by sponsor | 1 |
| Overall Study | Withdrawal by Subject | 9 |
Baseline characteristics
| Characteristic | Ribociclib 600 mg |
|---|---|
| Age, Continuous | 60.5 years STANDARD_DEVIATION 13.52 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status for participants Performance status = 0 | 36 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status for participants Performance status = 1 | 70 participants |
| Number of participants who had radiotherapy, surgery and liver metastasis Liver metastasis | 29 Participants |
| Number of participants who had radiotherapy, surgery and liver metastasis Prior antineoplastic radiotherapy | 61 Participants |
| Number of participants who had radiotherapy, surgery and liver metastasis Prior antineoplastic surgery | 92 Participants |
| Primary tumor type Adrenals | 1 Participants |
| Primary tumor type Bladder | 7 Participants |
| Primary tumor type Breast-triple negative | 7 Participants |
| Primary tumor type Cervix | 1 Participants |
| Primary tumor type Cholangio | 2 Participants |
| Primary tumor type Chordoma | 1 Participants |
| Primary tumor type Colorectal | 2 Participants |
| Primary tumor type Esophagus | 3 Participants |
| Primary tumor type Gall bladder ducts | 1 Participants |
| Primary tumor type Gastroesophageal junction | 4 Participants |
| Primary tumor type Gastrointestinal stromal tumor | 1 Participants |
| Primary tumor type Head and neck non-squamous cell carcinoma | 4 Participants |
| Primary tumor type Head and neck squamous cell carcinoma | 7 Participants |
| Primary tumor type Kidneys | 2 Participants |
| Primary tumor type Liver | 2 Participants |
| Primary tumor type Lung non-small cell adenocarcinoma | 9 Participants |
| Primary tumor type Lung non-small cell non-adenocarcinoma | 2 Participants |
| Primary tumor type Lung non-small cell squamous | 6 Participants |
| Primary tumor type Lymphoma | 1 Participants |
| Primary tumor type Mesothelioma | 5 Participants |
| Primary tumor type Neuroendocrine | 2 Participants |
| Primary tumor type Ovarian | 3 Participants |
| Primary tumor type Pancreas | 5 Participants |
| Primary tumor type Penile | 1 Participants |
| Primary tumor type Prostate | 1 Participants |
| Primary tumor type Salivary gland | 1 Participants |
| Primary tumor type Sarcoma | 13 Participants |
| Primary tumor type Skin non-melanoma | 3 Participants |
| Primary tumor type Thyroid | 1 Participants |
| Primary tumor type Unknown primary | 4 Participants |
| Primary tumor type Uterus | 4 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants |
| Race/Ethnicity, Customized Other | 7 Participants |
| Race/Ethnicity, Customized White | 90 Participants |
| Sex: Female, Male Female | 56 Participants |
| Sex: Female, Male Male | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 14 / 106 |
| other Total, other adverse events | 104 / 106 |
| serious Total, serious adverse events | 40 / 106 |
Outcome results
Primary
Clinical Benefit Rate (CBR) of ≥ 16 Weeks FAS
CBR was determined by local, Investigator assessment for each tumor assessment and defined as responses of CR + PR + SD for ≥ 16 weeks. CR and PR (for solid tumors) required a confirmation at least 4 weeks after the initial response observation. For hematologic tumors other appropriate hematological response criteria was applied. CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to \<10 mm, PR=At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study, PD=At least a 20% increase in the sum of diameter of all measured target lesions and also demonstrate an absolute increase of at least 5 mm FAS
Time frame: Baseline and ≥ 16 weeks up to approximately 36 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ribociclib 600 mg | Clinical Benefit Rate (CBR) of ≥ 16 Weeks FAS | 19 participant |
Primary
Number of Participants With Solid Tumor Response ≥ 16 Weeks for Based Upon Local Investigator Assessments
Clinical benefit (CB) for patients with solid tumors were assessed using RECIST 1.1 and included responses of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) for ≥ 16 weeks. CR and PR (for solid tumors) required a confirmation at least 4 weeks after the initial response observation. For hematologic tumors other appropriate hematological response criteria was applied. CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to \<10 mm, PR=At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study, PD=At least a 20% increase in the sum of diameter of all measured target lesions and also demonstrate an absolute increase of at least 5 mm. FAS
Time frame: Baseline up ≥16 weeks up to approximately 36 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ribociclib 600 mg | Number of Participants With Solid Tumor Response ≥ 16 Weeks for Based Upon Local Investigator Assessments | Complete response | 0 Participants |
| Ribociclib 600 mg | Number of Participants With Solid Tumor Response ≥ 16 Weeks for Based Upon Local Investigator Assessments | Partial response (PR) | 3 Participants |
| Ribociclib 600 mg | Number of Participants With Solid Tumor Response ≥ 16 Weeks for Based Upon Local Investigator Assessments | Stable disease (SD) | 16 Participants |
| Ribociclib 600 mg | Number of Participants With Solid Tumor Response ≥ 16 Weeks for Based Upon Local Investigator Assessments | Progressive disease (PD) | 71 Participants |
| Ribociclib 600 mg | Number of Participants With Solid Tumor Response ≥ 16 Weeks for Based Upon Local Investigator Assessments | Non-evaluable (NE) | 15 Participants |
Primary
Overall Response Rate (ORR) ≥ 16 Weeks. FAS
ORR was determined by local, Investigator assessment for each tumor assessment and defined as responses of CR+PR ≥ 16 weeks. FAS
Time frame: Baseline and ≥ 16 weeks up to approximately 36 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ribociclib 600 mg | Overall Response Rate (ORR) ≥ 16 Weeks. FAS | 3 participant |
Secondary
Number of Days for Duration of Response for Responders
Duration of response (DOR) is defined as time from the first documented response to the date first documented disease progression or relapse or death due to any cause. For patients with solid tumors the assessment criteria will be RECIST 1.1 and will include responses of CR and/or PR.
Time frame: Baseline up to approximately 36 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ribociclib 600 mg | Number of Days for Duration of Response for Responders | Patient 2 | 330 Days |
| Ribociclib 600 mg | Number of Days for Duration of Response for Responders | Patient 3 | 985 Days |
| Ribociclib 600 mg | Number of Days for Duration of Response for Responders | Patient 1 | 254 Days |
Secondary
Overall Survival (OS)
Number of participants Overall survival (OS) is defined as the time from the date of first dose to the date of death due to any cause.
Time frame: Baseline up to approximately 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib 600 mg | Overall Survival (OS) | 7.7 months |
Secondary
Progression Free Survival (PFS)
Progression-free survival (PFS) is the time from the date of start of treatment to the date of event defined as the first documented progression or death due to any cause within 30 days of the last dose. If a subject has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Progressive disease is defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (Note: the appearance of one or more new lesions is also considered progression)
Time frame: Every 8 weeks until death, assessed up to 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib 600 mg | Progression Free Survival (PFS) | 1.8 months |