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Label indication KISQALI FEMARA CO-PACK, a co-packaged product containing ribociclib, a kinase inhibitor, and letrozole, an aromatase inhibitor, is indicated: for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence. FDA label
Also known as Femara, FEM345
Letrozole · 20 trials · 16 indications
o The primary endpoint for chemotherapy versus no chemotherapy (R-T) is that the 5-year distant metastasis free survival (DMFS) of 92% will be tested (a one-sided test).
o The primary endpoint for the chemotherapy randomization (R-C) is disease free survival (DFS).
The primary test for the endocrine randomization (R-E) is DFS.
PFS defined as the time from the date of first IMP administration until the date of progression (recurrence) or death by any cause in the absence of progression. Assessment of progression (recurrence) is generally indicated by SYMPTOMS and will be assessed by the investigator most commonly on the basis of CT scans of the pelvis, abdomen and thorax, according to RECIST v1.1 criteria recommended and mostly presented by an elevated CA-125 level. Elevated CA-125 levels alone shouldn't be considered as progression. Progression assessment according to local standard of care, however, is similarly acceptable.
Change in bone mineral density (BMD) measured by dual X-ray absorptiometry (DXA) in lumbar spine (L1-L4). Change calculated by (Month 36 BMD-Baseline BMD)/Baseline BMD\*100.
Bone Mineral Density is measured by dual energy x-ray absorptiometry (DXA) scan. ANCOVA model was used in the analysis where: Variable = Baseline, Center, Treatment BMD = (Month 36 BMD-Baseline BMD)/Baseline BMD\*100.
BMD measured by DXA (dual energy x-ray absorptiometry) at lumbar spine, L1-L4. The T-Score is a comparison of a patient's BMD to that of a healthy 30 year of the same sex and ethnicity. The criteria of the World Health Organization are Normal is a T-Score of 1.0 or higher. Osteopenia is defined as between - 1.0 and -2.5. Osteoporosis is defined as -2.5 or lower, meaning a bone density that is two and half standard deviations below the mean of a 30 year old man/woman.
Bone Mineral Density is measured by dual energy x-ray absorptiometry (DXA). The Z-Score is the number of standard deviations a patient's BMD differs from the average BMD of their age, sex and ethnicity. A Z-score of less than minus -1.5 raises concern of factors other than aging as contributing to osteoporosis.
Disease-free survival was defined as the time from the date of randomization to the date of the first documentation of re-occurrence of invasive breast cancer in local, regional or distant sites, new invasive breast cancer in the contra-lateral breast, or death from any cause.
Lumbar spine (L2-L4) BMD measurements by dual energy X-ray absorptiometry (DXA) were performed after surgery and within 2 weeks prior to randomization and repeated every 6 months for the first 2 years and annually thereafter until 5 years after enrollment. The primary scanning site was the lumbar spine (L2 to L4) and the secondary scanning site was the total hip. All DXA scans were evaluated by a central reader.
Determine if ribociclib plus letrozole gives a ≥100% improvement in CCCA as compared to chemotherapy in the surgical specimen.
Objective response or stable disease rate monitored as patients accrue and are evaluated following the example of Thall and Simon. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
This outcome will report the number of patients who experienced a dose-limiting Toxicity (DLT) in Phase I Cohort 1, Phase I Cohort 2, and Phase I Cohort -1. A DLT was defined as: 1. A grade 3 or 4 non-hematologic toxicity except anorexia, alopecia, nausea (which is not refractory to antiemetics), fatigue, and fever without neutropenia; 2. Failure to recover to baseline (except alopecia) after delaying the next dose by more than 14 days; 3. Grade 3 or 4 neutropenia complicated by fever \>38.5°C or infection, or grade 4 neutropenia of ≥7 days duration; or 4. Grade 4 thrombocytopenia, or grade 3 thrombocytopenia complicated by hemorrhage. The maximum tolerated dose (MTD) is defined as the highest dose at which 0 out of the first 3 or 1 out of a total of 6 patients experience DLT during the first cycle of therapy; this dose level will be the recommended phase 2 dose (RP2D) in the Phase II Group.
The highest dose of the drug that does not cause unacceptable side effects. The maximum tolerated dose be testing increasing doses until the highest dose with acceptable side effects is found.
| Arm | Type | Description |
|---|---|---|
| Chemotherapy randomization: Arm I (anthracycline-based) | ACTIVE_COMPARATOR | * FEC 100 * Canadian CEF * CAF * FAC * E-CMF |
| Chemotherapy randomization: Arm II (docetaxel and capecitabine) | EXPERIMENTAL | * Docetaxel * Capecitabine |
| Endocrine therapy randomization: Arm I | ACTIVE_COMPARATOR | 2 years of tamoxifen followed by 5 years of letrozole |
| Endocrine therapy randomization: Arm II | EXPERIMENTAL | 7 years of letrozole |
| Treatment decision randomization: Arm I | ACTIVE_COMPARATOR | chemotherapy-decision-making according to clinical criteria (using Adjuvant! Online) |
| Treatment decision randomization: Arm II | EXPERIMENTAL | chemotherapy-decision-making according to genomic prognosis using the 70-gene signature |
| Letrozole (aromatase inhibitor) | EXPERIMENTAL | Letrozole, 2.5 mg Femara tablet, administered once daily for 5 years or until symptoms of toxicity or progression of underlying disease |
| Placebo | PLACEBO_COMPARATOR | Placebo tablet of Femara (without aromatase inhibitor), 0 mg Femara tablet, administered once daily for 5 years or progression of underlying disease |
| Letrozole | EXPERIMENTAL | - |
| Letrozole + Zoledronic Acid | EXPERIMENTAL | Letrozole orally 2.5mg/day for 3 years; Zoledronic acid 4mg every 6 months by infusion |
| Anastrozole | ACTIVE_COMPARATOR | 1 mg p.o. once daily |
| Tam-Let | EXPERIMENTAL | 20 mg Tamoxifen once daily (q.d.) orally for 2 years followed by Letrozole 2.5 mg q.d. orally for 3 years. |
| Advise letrozole, treatment choice free. | OTHER | All patients initially start with two weeks of letrozole treatment. Patients with a Ki67 of \<1% in the biopsy taken after those two weeks of treatment are advised to stay on letrozole treatment until surgery. However, treatment choice is free. |
| Chemotherapy | ACTIVE_COMPARATOR | All patients initially start with two weeks of letrozole treatment. Patients with a Ki67 of ≥1% in the biopsy taken after those two weeks of treatment are randomized between chemotherapy (standard AC-T chemotherapy) or ribociclib plus letrozole (ribociclib 600 mg/day (days 1-21, q4 weeks) plus letrozole 2.5 mg daily (days 1-28, q4 weeks)). |
| Ribociclib plus letrozole | EXPERIMENTAL | All patients initially start with two weeks of letrozole treatment. Patients with a Ki67 of ≥1% in the biopsy taken after those two weeks of treatment are randomized between chemotherapy (standard AC-T chemotherapy) or ribociclib plus letrozole (ribociclib 600 mg/day (days 1-21, q4 weeks) plus letrozole 2.5 mg daily (days 1-28, q4 weeks)). |
| Letrozole + RAD001 | EXPERIMENTAL | Letrozole and RAD001 (Everolimus) |
| Phase I Cohort 1 | EXPERIMENTAL | Letrozole 2.5 mg PO daily until surgery, everolimus 5 mg PO daily for 24 weeks, and TRC105 15 mg/kg IV q 2 weeks for 24 weeks |
| Phase I Cohort 2 | EXPERIMENTAL | Letrozole 2.5 mg PO daily until surgery, everolimus 10 mg PO daily for 24 weeks, and TRC105 15 mg/kg IV q 2 weeks for 24 weeks |
| Phase I Cohort -1 | EXPERIMENTAL | Letrozole 2.5 mg PO daily until surgery, everolimus 5 mg PO daily for 24 weeks, and TRC105 10 mg/kg IV q 2 weeks for 24 weeks |
| Phase II | EXPERIMENTAL | Letrozole 2.5 mg PO daily until surgery, everolimus 5 or 10 mg PO daily for 24 weeks, and TRC105 15 or 10 mg/kg IV q 2 weeks for 24 weeks. Dose and regimen to be determined based on data from the phase I component. |
| Sorafenib and Letrozole | EXPERIMENTAL | - |
| Name | Type | Description |
|---|---|---|
| anthracycline-based | DRUG | - |
| docetaxel and capecitabine | DRUG | - |
| tamoxifen | DRUG | - |
| Letrozole | DRUG | - |
| Letrozole 2.5mg | DRUG | Aromatase inhibitor |
| Placebo | OTHER | Placebo tablet of Femara |
| Zoledronic acid | DRUG | 4 mg every 6 months |
| Anastrozole | DRUG | 1 mg tablets |
| Chemotherapy | DRUG | Dose dense AC-T chemotherapy: consisting of 4 cycles of AC (doxorubicin and cyclophosphamide at a dose of 60 and 600 mg/m² as an i.v. bolus, respectively) 2-weekly, plus G-CSF (6 mg once per cycle) 24-48 hr after chemotherapy, followed by cycles of T (4 cycles docetaxel 100 mg/m² 3-weekly or 12 cycles paclitaxel 80 mg/m2 weekly). |
| Ribociclib plus letrozole | DRUG | Ribociclib 600 mg/day (days 1-21, q4 weeks) plus letrozole 2.5 mg daily (days 1-28, q4 weeks). |
| RAD001 (Everolimus) | DRUG | 10 mg by mouth daily |
| Everolimus | DRUG | The dose of everolimus will be escalated from 5 mg to 10 mg daily depending upon the cohort in Phase I. It is administered as an oral pill to be taken once daily up until four weeks prior to surgery. |
| TRC105 | DRUG | The dose for TRC105 is either 15 or 10 mg/kg to be given intravenously every two weeks and continued until four weeks prior to surgery. |
| Sorafenib | DRUG | sorafenib dose will be given at a daily dose to be determined based upon the phase of study that patient is enrolled The phase II dose of sorafenib will be determined from the phase I portion of the study. |
DISEASE CHARACTERISTICS: * Histologically confirmed invasive breast cancer meeting the following criteria: * T1, T2, or operable T3 disease * Zero to three positive lymph nodes and no distant metastases * Unilateral tumor * Multifocal tumors are allowed provided that they have identical...
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Letrozole is used in oncology for breast cancer and related conditions, including hormone sensitive resected primary breast cancer in postmenopausal women, metastatic breast cancer, breast neoplasms, and endometrial cancer. It is also studied in osteoporosis. It is a small molecule developed by Novartis AG.
Letrozole targets CYP19A1, also known as aromatase. It acts as an inhibitor of this enzyme, which is involved in estrogen biosynthesis. By inhibiting CYP19A1, Letrozole reduces estrogen production, which is relevant in hormone sensitive cancers such as breast cancer.
Letrozole is developed by Novartis AG, which trades under the ticker NVS. Novartis AG is the company associated with the development of this small molecule aromatase inhibitor.
Letrozole is in Phase 3 development. It is an investigational small molecule and has been studied in multiple clinical trials across different phases. The Phase 3 program includes a recruiting trial in ovarian, fallopian tube, and peritoneal cancers.
Letrozole has been studied in several clinical trials, including NCT04111978, a Phase 3 recruiting trial in ovarian, fallopian tube, and peritoneal neoplasms; NCT03283384, a Phase 2 active not recruiting trial in breast neoplasms; NCT02520063, a completed Phase 1 trial in breast cancer; and NCT01068249, a Phase 2 active not recruiting trial in endometrial cancer.