Clinical trial NCT03839823: Study to Compare the Combination of Ribociclib Plus Goserelin Acetate With Hormonal Therapy Versus Combination Chemotherapy in Premenopausal or Perimenopausal Patients With Advanced or Metastatic Breast Cancer
Official title: A Phase II Randomized Study of the Combination of Ribociclib Plus Goserelin Acetate With Hormonal Therapy Versus Physician Choice Chemotherapy in Premenopausal or Perimenopausal Patients With Hormone Receptor-positive/ HER2-negative Inoperable Locally Advanced or Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: HR-positive
HER2-negative
advanced breast cancer
Ribociclib
NSAI
Goserelin
Docetaxel / capecitabine
Paclitaxel/gemcitabine
Capecitabine/vinorelbine
CDK4/6 inhibitors
Phase II
ER-positive
PR-positive
Premenopausal
Perimenopausal
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2019-02-15
Enrollment: 222
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 59
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This was a randomized, phase II, open label, multi-center trial comparing the combination of NSAI (letrozole or anastrozole) + goserelin + ribociclib versus combination chemotherapy (either of docetaxel/capecitabine or paclitaxel/gemcitabine or capecitabine/vinorelbine). Premenopausal or perimenopausal women with HR+, HER2- negative, advanced breast cancer with ECOG performance status of 0 to 2 and having symptomatic visceral metastases, or rapid progression of disease or impending visceral compromise, or markedly symptomatic non visceral disease were considered for this study.
Primary purpose: TREATMENT

Brief summary: To compare the combination of Ribociclib plus goserelin acetate with hormonal therapy versus combination chemotherapy in premenopausal or perimenopausal patients with advanced or metastatic breast cancer

Detailed description: Patients were randomly assigned to one of the below treatment arms in 1:1 ratio:

* Ribociclib arm: non-steroidal aromatase inhibitor (NSAI) + goserelin + Ribociclib
* Combination chemotherapy arm: Either of docetaxel + capecitabine, paclitaxel + gemcitabine, or capecitabine + vinorelbine based chemotherapy treatment Randomization was stratified by (1) the presence of liver metastases (present or absent) (2) disease-free interval (DFI) \< 2 years (yes or no, de novo stage 4 was defined as DFI \> 2 years).

The study consisted of a 28-day Screening phase, treatment phase (including end of treatment (EOT) visit and safety follow-up), and survival follow-up. Patients received study treatment until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason.

Patients were followed for survival regardless of treatment discontinuation for any reason (except if consent was withdrawn, patient was lost to follow-up, or until death) and regardless of achieving the primary endpoint, until death, withdrawal of consent, or loss to follow-up.

Eligibility criteria: INCLUSION CRITERIA

1. Patient was an adult female ≥ 18 years old and \< 60 years old at the time of informed consent.
2. Patient had a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer based on the most recently analyzed tissue sample and all tested by local laboratory. ER should have been more than 10% ER positive or Allred ≥5 by local laboratory testing.
3. Patient had HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1 + or 2 + If IHC is 2 +, a negative in situ hybridization (FISH, CISH, or SISH) test was required by local laboratory testing and based on the most recently analyzed tissue sample.
4. Women with inoperable locally advanced or metastatic breast cancer not amenable to curative therapy. Patients had to fulfill at least one of the following criteria to be considered that combination chemotherapy was needed according to PI's judgment. However, for patients who were eligible under inoperable locally advanced breast cancer or criteria 4c, the recruitment was stopped to enrich patient population with visceral metastases.

   * Symptomatic visceral metastases
   * Rapid progression of disease or impending visceral compromise.
   * Markedly symptomatic non-visceral disease if the treating physician opted to give chemotherapy for rapid palliation of patient's symptoms.
5. Patient was premenopausal or perimenopausal at the time of study entry.

   1. Premenopausal status was defined as either:

      * Patient had last menstrual period within the last 12 months. OR
      * If on tamoxifen within the past 14 days, plasma estradiol and FSH were in the premenopausal range, according to local laboratory definition.
      * In case of therapy induced amenorrhea, plasma estradiol and/or FSH were in the premenopausal range according to local laboratory definition.
      * Patients who had undergone bilateral oophorectomy were not eligible.
   2. Perimenopausal status was defined as neither premenopausal nor postmenopausal.
6. Patients had received neither prior hormonal therapy nor chemotherapy for advanced breast cancer, except LHRH agonist. Patients who received ≤ 14 days of tamoxifen or a NSAI (letrozole or anastrozole) with or without LHRH agonist for advanced breast cancer prior to randomization were eligible. Patient had measurable disease.

EXCLUSION CRITERIA;

1. Patient received prior systemic anti-cancer therapy (including hormonal therapy and chemotherapy, or any CDK4/6 inhibitor for advanced breast cancer).

   * Patients who received (neo) adjuvant therapy for breast cancer were eligible. If the prior neo (adjuvant) therapy included aromatase inhibitors, the treatment-free interval must have been greater than 12 months from the completion of aromatase inhibitor treatment until randomization.
   * If patients had disease recurrence during adjuvant tamoxifen treatment, disease-free interval (defined as duration between the date of patient received complete tumor resection for primary breast cancer lesion to the date of disease recurrence documented) must have been greater than 12 months.
   * Patients who were receiving ≤ 14 days of tamoxifen or NSAI or LHRH agonists ≤ 28 days for advanced breast cancer prior to randomization were eligible.
2. Patient had received extended-field radiotherapy ≤ 2 weeks prior to randomization or limited field radiotherapy ≤ 2 weeks prior to randomization, and had not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion). Patient from whom ≥ 25% of the bone marrow had been previously irradiated were also excluded.
3. Patient had a concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated, basal or squamous cell skin carcinoma or curatively resected cervical cancer in situ.
4. Patients who had lung metastases with oxygen demand in resting status.
5. Patients who had liver metastases with bilirubin \> 1.5 ULN.
6. Patients with CNS involvement unless they met ALL of the following criteria:

   * At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment.
   * Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases.
   * Leptomeningeal metastases was not allowed, even with stable clinical condition.

Primary outcomes:
measure: Progression-free Survival
timeFrame: Up to approximately 34 months
Secondary outcomes:
measure: Time to Treatment Failure
timeFrame: Up to approximately 34 months
measure: 3-month Treatment Failure Rate
timeFrame: Up to approximately 3 months
measure: Overall Response Rate (ORR)
timeFrame: Up to approximately 34 months
measure: Clinical Benefit Rate
timeFrame: Up to approximately 34 months
measure: Time to Response
timeFrame: Up to approximately 34 months
measure: Overall Survival (OS)
timeFrame: Up to approximately 46 months
measure: Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire
timeFrame: Up to approximately 46 months
measure: Number of Patients With Adverse Events, Categorized by Severity
timeFrame: Up to approximately 46 months
measure: Number of Patients With Laboratory Abnormalities
timeFrame: Up to approximately 46 months
measure: Post-Hoc: All Collected Deaths
timeFrame: On-treatment deaths: Up to approximately 46 months. Post-treatment survival follow-up deaths: Up to approximately 2 additional months.
Other outcomes:
Locations:
city: Cairo
country: Egypt
facility: Novartis Investigative Site
city: Cairo
country: Egypt
facility: Novartis Investigative Site
city: Cairo
country: Egypt
facility: Novartis Investigative Site
city: Giza
country: Egypt
facility: Novartis Investigative Site
city: Bangalore
country: India
facility: Novartis Investigative Site
state: Karnataka
city: Pune
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Hyderabad
country: India
facility: Novartis Investigative Site
state: Telangana
city: Kolkata
country: India
facility: Novartis Investigative Site
state: West Bengal
city: Mumbai
country: India
facility: Novartis Investigative Site
city: New Delhi
country: India
facility: Novartis Investigative Site
city: Amman
country: Jordan
facility: Novartis Investigative Site
city: Beirut
country: Lebanon
facility: Novartis Investigative Site
city: Saida
country: Lebanon
facility: Novartis Investigative Site
city: Tripoli
country: Lebanon
facility: Novartis Investigative Site
city: Johor Bahru
country: Malaysia
facility: Novartis Investigative Site
state: Johor
city: Kota Kinabalu
country: Malaysia
facility: Novartis Investigative Site
state: Sabah
city: Kuching
country: Malaysia
facility: Novartis Investigative Site
state: Sarawak
city: Kuala Lumpur
country: Malaysia
facility: Novartis Investigative Site
state: Wilayah Persekutuan
city: Pulau Pinang
country: Malaysia
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Pushkin Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: St Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Riyadh
country: Saudi Arabia
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Durban
country: South Africa
facility: Novartis Investigative Site
state: Kwazulu Natal
city: Pretoria
country: South Africa
facility: Novartis Investigative Site
city: Pretoria
country: South Africa
facility: Novartis Investigative Site
city: Kaohsiung
country: Taiwan
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan
country: Taiwan
facility: Novartis Investigative Site
city: Songkhla
country: Thailand
facility: Novartis Investigative Site
state: Hat Yai
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Chiang Mai
country: Thailand
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Antalya
country: Turkey
facility: Novartis Investigative Site
city: Cankaya Ankara
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Kecioren Ankara
country: Turkey
facility: Novartis Investigative Site
city: Malatya
country: Turkey
facility: Novartis Investigative Site
city: Hanoi
country: Vietnam
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: