Clinical trial NCT03227328: CDK4/6-inhibitor or Chemotherapy, in Combination with ENDOcrine Therapy, for Advanced Breast Cancer / KENDO
Official title: Group Sequential Response Adaptive Randomized Clinical Trial of Concomitant Chemotherapy Plus Endocrine Therapy Versus Cyclin-dependent Kinase 4/6 (CDK4/6) Inhibitor Plus Endocrine Therapy for Advanced Hormone Receptor-positive, HER2-negative Breast Cancer.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hormone Receptor Positive Breast Cancer
Metastatic Breast Cancer
Hormone Receptor Negative Breast Cancer
Keywords: HR-positive Breast Cancer
metastatic breast cancer
First line treatment
endocrine therapy
chemotherapy
randomized phase III trial
aromatase inhibitor
HR-negative Breast Cancer
CDK4/6 inhibitor
Lead sponsor: Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRST S.r.l. IRCCS
Sponsor class: OTHER
Collaborators: name: Agenzia Italiana del Farmaco
First posted: 2017-07-24
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: group sequential response adaptive Randomized, open label, multicenter,
Primary purpose: TREATMENT

Brief summary: Prospective, open label, multicenter, group sequential response adaptive randomized phase 2 study, comparing two treatments for locally advanced or metastatic luminal breast cancer:

* Arm A: concomitant cyclin-dependent Kinase 4/6 (CDK4/6) inhibitor (palbociclib, ribociclib or abemaciclib) plus endocrine therapy (aromatase inhibitor \[AI\] or fulvestrant)
* Arm B: chemotherapy plus endocrine therapy (AI or fulvestrant, administered either concomitantly from the beginning of chemotherapy or sequentially after 4-6 months of chemotherapy) Treatments will continue until disease progression or toxicity or patient refusal.

Detailed description: Group sequential response adaptive randomized clinical trial of concomitant chemotherapy plus endocrine therapy versus cyclin-dependent Kinase 4/6 (CDK4/6) inhibitor plus endocrine therapy for advanced hormone receptor-positive, HER2-negative breast cancer Primary Objective: To compare the efficacy of concomitant CDK4/6 inhibitor plus endocrine therapy versus chemotherapy plus endocrine therapy (administered either concomitantly from the beginning or sequentially) in terms of progression-free survival (PFS).

Secondary objectives: To compare between treatment arms:

* quality of life (EORTC quality of life questionnaire(QLQ) QLQ -C30 and QLQ-BR23)
* toxicity (CTCAE version 5.0)
* time to treatment failure
* best response rate
* duration of response
* clinical benefit rate
* overall survival (OS)
* PFS and clinical benefit with the subsequent line of treatment after cross-over: CDK4/6 inhibitors plus endocrine therapy in patients treated with chemotherapy plus endocrine therapy, chemotherapy (with or without endocrine therapy) in patients treated with CDK4/6 inhibitors plus endocrine therapy
* correlative biomarkers of response to CDK4/6 inhibitors and chemotherapy:

  * tissue markers (on the primary tumor and / or metastatic tissue)
  * circulating markers (e.g. CTCs, ctDNA)

The patients will be allocated according to block randomization until two events are observed in each arm, and then according to the time-to-event adaptation of the group sequential Doubly-adaptive Biased Coin Design (DBCD) whose allocation probabilities are computed at the end of the block randomization and after around 70% and 85% of the 150 maximum patients are enrolled during a 23 month period. At these last two (i.e. after 105 and 128 patients, respectively), interim analysis on efficacy will be carried out allowing for early stopping. At the end of the 16-month follow up, administrative censoring is introduced. Therefore, the total study duration is 39 months.

Previous results on palbociclib and fulvestrant combination in second line and the characteristics of our target population lead us to assume a median PFS of 8 and 12 months for arm A and B, respectively. Under this scenario, for a sample size of at the most 150 patients, the proposed design strategy has led to a simulated power of 0.911 compared with a 0.717 one for the Complete Randomisation design.

Eligibility criteria: Inclusion Criteria:

* Histological diagnosis of HR-positive (ER ≥10% of tumor cells), HER2-negative breast cancer, determined by local laboratory on most recent available tumor tissue.
* Locally advanced (not susceptible to locoregional therapy) or metastatic disease (herein globally defined as "advanced breast cancer (ABC)").
* At least one of the following signs of disease aggressiveness:

  * The main criteria are a low expression of ER (10% ≤ ER \< 50%) and/or a relapse while on the first 2 years of adjuvant endocrine therapy or disease progression (PD) within the first 6 months of first-line endocrine therapy for ABC
  * Other tumor characteristics of aggressiveness that make the patient potentially candidate to chemotherapy, according to the guidelines of the Italian Association of Medical Oncology \[AIOM guidelines 2017\], such as: elevated Ki67 (preferably documented, if available, on a metastatic biopsy), low expression of hormone receptors (e.g. progesterone receptor \<20%), extended visceral involvement or visceral involvement at risk for organ failure, uncontrolled symptoms; these patients are eligible if chemotherapy is considered a suitable option by the treating physician.
* Postmenopausal women, or premenopausal women undergoing treatment with LHRH analog, or men (either receiving treatment with LHRH analog or not).
* Measurable disease according to RECIST 1.1 criteria, or not measurable but evaluable disease.
* Any prior adjuvant chemotherapy or endocrine therapy
* No prior chemotherapy for advanced disease.
* Up to one prior line of endocrine therapy for ABC.
* Age ≥ 18 years.
* Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤2 (see Appendix A).
* Adequate organ (renal, hepatic, bone marrow, cardiac) functions.
* Female participants of child bearing potential and male participants whose partner is of child bearing potential must be willing to use effective contraception during the study period and for 4 months thereafter. Effective contraception methods include: total abstinence (when this is in line with the preferred and usual lifestyle of the subject); tubal ligation; male sterilization; combination of the placement of an intrauterine device or intrauterine system and barrier methods of contraception with spermicidal suppository.
* Participant is willing and able to give informed consent for participation in the study.

Exclusion Criteria:

* Any prior chemotherapy or CDK4/6 inhibitor for advanced breast cancer
* More than 1 prior line of endocrine therapy for ABC.
* Patients who have not recovered from adverse events due to prior therapies to grade ≤1 (excluding alopecia).
* Active central nervous system metastases.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to the drugs used in the study.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Prior history of non-breast malignancy (except for adequately controlled basal cell carcinoma of the skin, carcinoma in situ of the cervix, in situ carcinoma of the bladder), unless treated with curative intent and disease free for at least 3 years.

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: up to 39 months
Secondary outcomes:
measure: EORTC QLQ-C30 quality of life between the 2 arms
timeFrame: up to 39 months
measure: QLQ-BR23 quality of life between the 2 arms
timeFrame: up to 39 months
measure: toxicity
timeFrame: up to 39 months
measure: time to treatment failure (TTF)
timeFrame: up to 39 months
measure: best objective response rate
timeFrame: up to 39 months
measure: duration of response
timeFrame: up to 39 months
measure: clinical benefit rate (CBR)
timeFrame: up to 39months
measure: overall survival (OS)
timeFrame: up to 39 months
measure: Progression free survival (PFS)
timeFrame: up to 39 months
measure: correlative biomarkers of response to chemotherapy and endocrine therapy
timeFrame: up to 39 months
Other outcomes:
Locations:
city: Bologna
country: Italy
facility: U.O. Oncologia Medica, P.O. Bellaria-Maggiore
state: BO
city: Meldola
country: Italy
facility: UO Oncologia Medica IRST IRCCS
state: FC
city: Carpi
country: Italy
facility: Dip. Medicina Interna e Riabilitazione - U.O. Medicina Interna Oncologica, Ospedale Ramazzini
state: MO
city: Piacenza
country: Italy
facility: Dip. Oncologia-Ematologia - U.O. Oncologia Medica,Azienda USL di Piacenza - Ospedale Civile
state: PC
city: Ravenna
country: Italy
facility: UOC Oncologia Medica AUSL Romagna-Ravenna
state: RA
city: Rimini
country: Italy
facility: UO Oncologia Medica AUSL Romagna-Rimini
state: RI
city: Ancona
country: Italy
facility: A.O.U. Ospedali Riuniti Umberto I - GM Lancisi - G Salesi
city: Bari
country: Italy
facility: U.O. Oncologia Medica; Ist. Tumori Giovanni Paolo II - IRCCS Osp. Oncologico di Bari
city: Cremona
country: Italy
facility: Terapia Molecolare e Farmaco Genomica, Azienda Socio-Sanitaria Territoriale di Cremona
city: Ferrara
country: Italy
facility: A.O.U. di Ferrara Arcispedale Sant'Anna
city: Guastalla
country: Italy
facility: Ospedale Civile di Guastalla - AUSL di Reggio Emilia
city: Imola
country: Italy
facility: AUSL Imola
city: Legnago
country: Italy
facility: Ospedale Mater Salutis - Azienda ULSS9 Scaligera
city: Macerata
country: Italy
facility: Ospedale di Macerata, ASUR AV3
city: Modena
country: Italy
facility: A.O.U. Policlinico di Modena
city: Novara
country: Italy
facility: A.O.U. Maggiore della Carità di Novara
city: Parma
country: Italy
facility: U.O. Oncologia Medica, AOU di Parma
city: Perugia
country: Italy
facility: A.O. Santa Maria della Misericordia di Perugia
city: Reggio Emilia
country: Italy
facility: A.O. Arcispedale S. Maria Nuova IRCCS di Reggio Emilia
city: Sondrio
country: Italy
facility: Ospedale di Sondrio - ASST Valtellina e Alto Lario
Study officials:
affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Via Maroncelli 40, 47014 Meldola, ITALY
name: Andrea Rocca
role: STUDY_DIRECTOR
References: