PHASE II STUDY TO EVALUATE THE EFFICACY AND SAFETY OF CAMIZESTRANT PLUS RIBOCICLIB IN PATIENTS WITH HORMONE RECEPTOR-POSITIVE (HR+) BREAST CANCER (THE CADILLAC STUDY)

Trial ID: 2024-520027-88-00
Protocol: MEDOPP0555
Sponsor: Medica Scientia Innovation Research S.L.

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Diseases & Conditions

Hormone receptor positive breast cancer

Objectives

The primary objective is to determine the median progression-free survival (PFS) as assessed locally by the investigator in patients with hormone receptor-positive (HR+)/HER2-negative advanced breast cancer treated with camizestrant plus ribociclib, compared to PFS data obtained from a historical control arm. This endpoint is clinically relevant as it measures the time during which the disease does not worsen under the investigational treatment regimen, providing evidence of therapeutic benefit in this patient population.

The secondary objectives include:

• Assessment of efficacy parameters including objective response rate (ORR), clinical benefit rate (CBR), time to response (TTR), time to subsequent line of chemotherapy (TTSLC), duration of response (DoR), and best percentage of change in tumor burden according to RECIST v.1.1 criteria in all patients receiving the combination treatment.

• Description of changes in health-related quality of life (HRQoL) from baseline using validated instruments including the EORTC QLQ-C30, breast cancer-specific QLQ-BR42, PRO-CTCAE, Global Items (PGIS, PGIC, PGITT), and EQ-5D-5L questionnaires.

• Determination of the safety and toxicity profile according to NCI-CTCAE v.5.0 criteria for the combination of camizestrant and ribociclib in all patients.

• Comparison of locally assessed efficacy endpoints in HR+/HER2- advanced breast cancer patients treated with camizestrant plus ribociclib against efficacy endpoints obtained from real-world databases.

• Evaluation of the impact of estrogen receptor 1 (ESR1) gene mutations on both PFS and overall survival (OS).

• Assessment of the association between disease activity status, patient outcomes, or response to study treatment with predictive, prognostic, and/or pharmacodynamic biomarkers analyzed in blood and tumor tissue samples.

• Determination of the association between treatment efficacy and/or safety outcomes with radiological imaging biomarkers.

Participants

This clinical trial enrolled a total of **57 participants** diagnosed with **hormone receptor-positive (HR+)** and **human epidermal growth factor receptor 2 (HER2)-negative** advanced **breast cancer**. The study population included both female and male patients aged **18 years or older**. Eligible participants were required to have an **ECOG performance status** of 0-1 and a minimum life expectancy of at least 6 months. The trial population was selected based on documented histologically confirmed HR+ and HER2-negative breast cancer status according to ASCO/CAP guidelines, with tumors showing at least 10% of cells staining positive for **estrogen receptor** on **immunohistochemistry**. Participants had **unresectable locally recurrent or metastatic disease** confirmed by imaging that was not amenable to curative resection. Key selection criteria included prior receipt of at least five years of **adjuvant endocrine therapy**, with at least two years of an **aromatase inhibitor**, and radiological evidence of disease progression either during or within a specified timeframe after completion of endocrine therapy. Female participants could be **post-menopausal**, **pre-menopausal**, or **peri-menopausal** if treated with a **luteinizing hormone-releasing hormone (LHRH) analogue**. Participants were required to have adequate bone marrow and organ function, including specific hematological, hepatic, and renal parameters. The trial required availability of tumor tissue samples for analysis and excluded patients who had received certain prior therapies without appropriate washout periods.

Plans and Procedures

This is a Phase II clinical trial evaluating the efficacy and safety of camizestrant in combination with ribociclib in patients with hormone receptor-positive breast cancer. The trial employs a single-arm, open-label design with a historical control comparison. The primary objective is to determine the median progression-free survival (PFS) in patients with HR+/HER2- advanced breast cancer treated with the combination therapy, as assessed locally by the investigator according to RECIST v.1.1 criteria, and to compare these results with PFS data obtained from a historical control arm. The trial is designed to enroll patients who have received at least five years of adjuvant endocrine therapy, including at least two years of an aromatase inhibitor, and who have experienced disease progression either during or after completion of adjuvant treatment.

The study involves the administration of camizestrant, a synthetic selective estrogen receptor degrader (SERD), at a maximum daily dose of 75 mg, and ribociclib, a small molecule synthetic drug, at a maximum daily dose of 600 mg. Both investigational products are administered orally as film-coated tablets. The maximum treatment period is 27 months, with a maximum total dose of 60,900 mg for camizestrant and 365,400 mg for ribociclib. Treatment continues until disease progression, unacceptable toxicity, or other discontinuation criteria are met.

Eligible participants must be female or male patients aged 18 years or older with an ECOG performance status of 0-1 and a minimum life expectancy of 6 months. Patients must have documented histologically confirmed HR+ and HER2-negative breast cancer according to the most recent ASCO/CAP guidelines, defined as ≥10% of tumor cells staining positive for estrogen receptor on immunohistochemistry and HER2 negativity confirmed by appropriate testing. Participants must have unresectable locally recurrent or metastatic disease confirmed by CT scan or MRI that is not amenable to resection with curative intent. Evidence of measurable disease according to RECIST v.1.1 or nonmeasurable but evaluable disease, including bone-only disease with at least one lytic or mixed lytic-blastic bone lesion, is required.

Participants must demonstrate adequate bone marrow and organ function at baseline, including hematological parameters without recent transfusion or growth factor support, hepatic function with specific limits for bilirubin, alkaline phosphatase, AST, and ALT, and renal function with serum creatinine ≤1.5 × ULN or estimated creatinine clearance ≥50 mL/min. Pre- or peri-menopausal women or men are eligible if treated with a LHRH analogue for at least 28 days prior to study treatment, or if post-menopausal levels of serum estradiol/FSH are confirmed. Post-menopausal women are defined by cessation of menses for at least 12 consecutive months or documented bilateral surgical oophorectomy. Patients must agree to provide a FFPE tissue biopsy sample taken at the time of presentation with recurrent or metastatic disease, or an archived primary breast cancer specimen if recent tissue is unavailable. Women of childbearing potential and male participants must agree to use highly effective contraception methods during the study and for specified periods after the last dose of study treatment.

The study includes a screening visit to assess eligibility criteria, including medical history, physical examination, laboratory assessments, radiological imaging, and collection of tissue samples for biomarker analysis. Following enrollment, participants receive continuous treatment with the combination therapy and attend regular follow-up visits for safety monitoring, efficacy assessments, and collection of patient-reported outcomes. Study visits include clinical evaluations, laboratory tests, adverse event monitoring according to NCI-CTCAE v.5.0, tumor assessments by imaging, and administration of quality of life questionnaires including EORTC QLQ-C30, QLQ-BR42, PRO-CTCAE, Global Items (PGIS, PGIC, PGI-TT), and EQ-5D-5L. An end-of-study visit is conducted upon treatment discontinuation or study completion to perform final safety and efficacy assessments.

Secondary endpoints include overall response rate (ORR), defined as the rate of patients achieving complete response or partial response; clinical benefit rate (CBR), defined as the rate of patients with objective response or stable disease for at least 24 weeks; time to response (TTR); duration of response (DoR); best percentage change from baseline in target tumor lesion size; time to subsequent line of chemotherapy (TTSLC); changes in patient-reported outcomes; and safety and tolerability profiles. Additional exploratory endpoints include comparison of efficacy endpoints with real-world database results, Kaplan-Meier estimates of PFS and overall survival (OS) stratified by ESR1 mutation status, and biomarker analyses including mutation profiling, copy number variability, gene expression, multiplex assays, proteomic analyses, digital pathology, immunohistochemistry, and taxonomic or functional analyses in blood and tumor tissue samples to determine potential relationships with clinical outcomes, safety, and tolerability profiles. Association of treatment outcomes with radiological imaging biomarkers is also evaluated.

The estimated recruitment start date is December 31, 2025, and the estimated study end date is August 31, 2031, resulting in an overall trial duration of approximately 5 years and 8 months. Participant involvement extends from the screening visit through the treatment period and follow-up assessments until disease progression, death, withdrawal of consent, or study completion. Conditions that may lead to early termination from the study include disease progression as determined by RECIST v.1.1 criteria, unacceptable toxicity or adverse events that preclude continuation of treatment, withdrawal of informed consent, investigator decision based on safety concerns, pregnancy, protocol non-compliance, or death. Participants who discontinue study treatment for reasons other than disease progression continue to be followed for survival and subsequent anticancer therapy information.

Treatment

The investigational treatment regimen consists of two experimental medications administered in combination. **Ribociclib**, a small molecule synthetic drug, is formulated as a **film-coated tablet** for **oral** administration. The maximum daily dose is **600 mg**, with a maximum total dose of **365,400 mg** over a maximum treatment period of **27 months**. Ribociclib contains the active substance ribociclib of chemical origin.

**Camizestrant** (sponsor product code **AZD9833**) is a synthetic selective **estrogen receptor degrader** formulated as a film-coated tablet for oral administration. The maximum daily dose is **75 mg**, with a maximum total dose of **60,900 mg** over a maximum treatment period of 27 months. Camizestrant contains the active substance camizestrant of chemical origin. This medication is manufactured by AstraZeneca AB.

Both investigational products are administered orally and are not paediatric formulations. The combination therapy is being evaluated in patients with **hormone receptor-positive** and **HER2-negative advanced breast cancer**. The study objective is to determine the median **progression-free survival** in patients treated with camizestrant plus ribociclib as compared to progression-free survival data obtained from historical control arm, with efficacy assessed locally by the investigator.

Efficacy

Efficacy will be assessed using multiple parameters to evaluate the treatment outcomes in patients with **hormone receptor-positive** breast cancer. The primary efficacy endpoint is **progression-free survival (PFS)**, defined as the time from the date of the first dose until disease progression or death from any cause, whichever occurs first, as determined locally by the investigator using RECIST v.1.1. PFS will be compared to data obtained from a historical control arm.

Secondary efficacy endpoints include **objective response rate (ORR)**, defined as the rate of patients with complete response or partial response, as determined locally by the investigator using RECIST v.1.1. **Clinical benefit rate (CBR)** will be assessed as the rate of patients with objective response or stable disease for at least 24 weeks. **Time to response (TTR)** is defined as the period from treatment initiation to the first objective tumor response, observed for patients who achieved a complete response or partial response. **Duration of response (DoR)** will be measured as the period from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first. The best percentage of change from baseline in the size of target tumor lesions will be evaluated, defined as the biggest decrease or smallest increase if no decrease is observed. **Time to subsequent line of chemotherapy (TTSLC)** is defined as the period from treatment initiation to the subsequent line of chemotherapy. All tumor assessments will be performed locally by the investigator using RECIST v.1.1.

Additional efficacy assessments include changes from baseline in quality of life questionnaires, specifically the EORTC QLQ-C30, the breast cancer-specific QLQ-BR42, PRO-CTCAE, Global Items, and EQ-5D-5L. Efficacy endpoints for all patients will be compared to efficacy endpoints obtained from real world databases. Kaplan-Meier estimates of PFS and hazard ratio will be calculated for patients with **ESR1 mutation** detected versus non-detected. Kaplan-Meier estimates of overall survival and hazard ratio will also be determined for patients with ESR1 mutation detected versus non-detected. Mutation profiling, copy number variability, gene expression, multiplex assays, proteomic analyses, digital pathology, immunohistochemistry, and taxonomic or functional analyses may be performed in blood and tumor tissue samples to determine their potential relationship with clinical outcomes. The association of treatment efficacy outcomes with radiological imaging biomarkers will be evaluated.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient must be capable of understanding the purpose of the Study and have signed the written informed consent form (ICF) prior to beginning specific protocol procedures.
Female or male patients ≥ 18 years of age at the time of signing ICF.
Pre- or peri-menopausal women or men. are eligible if treated with a Luteinizing hormone-releasing hormone (LHRH) analogue. Treatment with a LHRH is recommended for at least 28 days prior to study treatment; if shorter, post-menopausal levels of serum estradiol/follicle-stimulating hormone [FSH] must be confirmed analytically prior to Study enrollment.
Post-menopausal women, defined by any of the following criteria: o Cessation of menses for at least 12 consecutive months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. o Documented bilateral surgical oophorectomy.
Documented histologically confirmed HR+ and human epidermal growth factor receptor 2 (HER2)-negative breast cancer according to the most recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines as per local assessment on the most recent analyzed biopsy. Therefore, tumors must be: o HR+ defined as ≥ 10% of tumor cells stain positive for estrogen receptor (ER) on immunohistochemistry (IHC), and HER2- defined as 0 or 1+ intensity on IHC, or 2+ intensity on IHC and no evidence of amplification on in situ hybridization (ISH).
Unresectable locally recurrent or metastatic disease confirmed by computerized tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to resection with curative intent.
Patients must have received at least five years of adjuvant endocrine therapy, including at least two years of an AI (capped to 30% patients with treatment-free interval [TFI] ≥ 12 months.
Patients must have: - Radiological evidence of progression while on, or within 12 months of the end of (neo)adjuvant endocrine therapy (secondary endocrine resistance criteria), or - Radiological evidence of progression more than 12 months of the end of (neo)adjuvant endocrine therapy (endocrine sensitive criteria).
Patients receiving a CDK4/6 inhibitor-based therapy in the (neo)adjuvant setting are eligible if disease progression is confirmed more than 12 months following CDK4/6 inhibitor treatment completion in this scenario.
Evidence of measurable disease as per RECIST v.1.1, or nonmeasurable, but evaluable, disease, including bone-only disease with at least one lytic or mixed lytic-blastic bone lesion.
For patients receiving tamoxifen or toremifene, a washout period of 35 days (5 half-lives) prior to randomization is required
Patients must agree to provide and have available a FFPE tissue biopsy sample taken at the time of presentation with recurrent or metastatic disease. If this is not available, archived primary breast cancer specimen may be submitted
Adequate bone marrow and organ function: - Hematological (without platelet, red blood cell transfusion, and/or granulocyte colony-stimulating factor support within seven days before treatment initiation): White blood cell (WBC) count > 3.0 x 10^9 /L; absolute neutrophil count (ANC) ≥ 1.5 x 10^9 /L; platelet count ≥ 100.0 x10^9 and hemoglobin ≥ 9.0 g/dL. - Hepatic: Serum albumin ≥ 2.5 g/dL; total serum bilirubin < 1.5 x upper limit of normal (ULN) except for patients with Gilbert’s syndrome who may be included if the total serum bilirubin is ≤ 3 x ULN or direct bilirubin ≤ 1.5 x ULN; alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 3 x ULN in patients with liver and/or bone metastases); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 x ULN (≤ 3 x ULN in patients with liver metastases); international normalized ratio (INR) < 1.5. Prothrombin time (PT) or Prothrombin time-international normalized ratio (PT-INR) and activated partial thromboplastin time (aPTT)/partial thromboplastin time (PTT) ≤ 1.5 × ULN, factor Xa inhibitors, or other similar anticoagulant therapy, who must have PT-INR within therapeutic range as deemed appropriate by the Investigator from product safety requirements (PSR). - Renal: Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 50 mL/min as calculated by Cockcroft-Gault equation.
Patient must be available and willing to participate in the treatment and follow-up assessments as required.
Women of childbearing potential who are sexually active with a non-sterilized male partner must have a negative serum pregnancy test within 14 days before Study treatment initiation. In addition, they must agree to use one highly effective method of birth control from the time of screening until 4 weeks after the last dose of Study treatments. Female patients must refrain from egg cell donation and breastfeeding during this same period. Non-sterilized male partners of heterosexually active females of childbearing potential participants must use a male condom from the time of enrollment of their female partner, throughout their participation in the Study, and until 4 weeks after their female partner’s last dose of Study intervention.
Male participants who are sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable highly effective method of contraception from the time of screening until 21 days after the last administration of the Study drug. Male participants must not donate or bank sperm during this same period. Female partners of childbearing potential of male participants must agree to use one highly effective method of contraception from the time of screening until 4 weeks after the last dose of Study treatments.
ECOG performance status of 0-1.
Minimum life expectancy of ≥ 6 months.

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Exclusion Criteria

Formal contraindication to endocrine therapy defined as visceral crisis and/or rapidly or symptomatic progressive visceral disease.
Current participation in another therapeutic clinical trial.
Has previously been treated with any SERD, including camizestrant, experimental ETs or fulvestrant.
Prior systemic therapy for advanced disease.
Known active uncontrolled or symptomatic central nervous system (CNS) metastases and/or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases are eligible if they have been previously treated with local therapy, are clinically stable, and off anticonvulsants and steroids for at least 14 days before the first dose of Study treatment.
History of another primary malignancy except for the following: a. Malignancy treated with curative intent with no known active disease ≥ 3 years before the first dose of Study treatment, and of very low potential risk for recurrence. b. Adequately treated non-melanoma skin cancer or lentigo malignancy without evidence of disease. c. Other exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin. Note: For other cancers considered to have a low risk of recurrence, discussion with the Medical Monitor is required.
Known allergy or hypersensitivity reaction to any investigational medicinal products (IMPs) or their incorporated substances. Note: Ribociclib is contraindicated for patients with hypersensitivity/allergy to peanut or soya.
History of malabsorption syndrome or other condition that would interfere with enteral absorption (ongoing gastrointestinal obstruction/motility disorder, malabsorption syndrome, or prior gastric bypass) or results in the inability or unwillingness to swallow pills.
Palliative radiotherapy with a limited field of radiation within two weeks or with wide field of radiation or radiation to more than 30% of the bone marrow within four weeks prior to Study enrollment.
Major surgical procedure or significant traumatic injury within 14 days before Study enrollment or anticipation of need for major surgery within the course of the Study treatment.
Cardiac symptoms, procedures, or test results as follows: Unexplained syncope (within the last six months prior to Study enrollment), or ongoing symptomatic hypotension, or ongoing asymptomatic hypotension with blood pressure systolic < 90 mmHg. Second- and third-degree heart block, or clinically significant sinus pause or sinoatrial block. Patients with pacemakers or medically controlled atrial fibrillation are not excluded. Factors that increase the risk of QTc prolongation or the risk of arrhythmic events such as symptomatic heart failure, congenital long QT syndrome, immediate family history of long QT syndrome, unexplained sudden death < 40 years of age, hypertrophic cardiomyopathy and clinically significant stenotic valve disease. Known left ventricular ejection fraction (LVEF) <50% with heart failure NYHA Grade ≥ 2. Untreated electrolyte abnormalities with potential QT-prolonging effect including altered levels of serum/plasma potassium, magnesium, and calcium. Note: Correction of electrolyte abnormalities to within normal ranges can be performed during the screening period. Mean resting QTcF interval > 450 ms, obtained from triplicate-ECG performed at screening. Resting heart rate consistently 50-90 bpm. Repeat measurements are permitted during the screening period. Uncontrolled hypertension. Blood pressure systolic > 160 and diastolic > 90 mmHg despite optimal medical management. Note: Hypertensive patients may be eligible, but blood pressure must be adequately controlled at baseline. Experience of any of the following procedures or conditions in the preceding six months: coronary artery bypass graft, angioplasty, vascular stent, any other structural heart disease interventions (e.g., cardiac valve repair or replacement surgery or transcatheter valve treatment), severe aortic regurgitation (Grades 3 and 4), myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischemic attack.
Known abnormalities in coagulation such as bleeding diathesis, or any history of coagulopathy within six months before Study enrollment, including history of deep vein thrombosis or pulmonary embolism.
Patients treated: Within 2 weeks prior to first dose: medications or herbal supplements known to be strong inhibitors/inducers of cytochrome P450 (CYP) 3A4/5, sensitive CYP2B6 substrates, and drugs which are substrates of CYP2C9 and/or CYP2C19 which have a narrow therapeutic range (e.g. warfarin/phenytoin) or who have not fully recovered from side effects of such treatment. With medications that are known to prolong the QT interval and have a known risk of Torsades de Pointes.
Pregnant or lactating women or patients not willing to apply highly effective contraception as defined in the protocol.
Current known infection with human immunodeficiency virus (HIV) detectable viral load, hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
Any other active uncontrolled infection at the time of screening.
Known substance abuse or any other concurrent severe and/or uncontrolled psychiatric or medical condition that would, in the Investigator’s judgment, contraindicate patient participation.