SEQUEL-Breast: a phase 2 study on the combination of alpelisib and fulvestrant after progression on previous therapy with fulvestrant in patients with PIK3CA-mutated, hormone-receptor positive, HER2 negative advanced breast cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

BOOG Study Center B.V.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 Jun 2022 → ongoing

Decision date (initial)

2024-09-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-514965-20-00

EudraCT number

2021-004191-33

ClinicalTrials.gov

NCT05392608

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To investigate the efficacy of the combination of fulvestrant and alpelisib directly after progression on 1st or 2nd line therapy with fulvestrant (monotherapy or in combination with a CDK 4/6 inhibitor) in pre- or postmenopausal women and men with HR+HER2- advanced breast cancer with tumors harboring an activating PIK3CA mutation. Previous treatment with a CDK 4/6 inhibitor (either in 1st or 2nd line) is mandatory.

Conditions and MedDRA coding

Breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Adult women and men 18 years of age) with proven diagnosis of adenocarcinoma of the breast with locoregional recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent and for whom chemotherapy is not clinically indicated. Women must be postmenopausal, have had a bilateral oophorectomy, or receive an luteinizing hormone releasing hormone (LHRH)analogue. Men must receive an LHRH-analogue.
2. Documentation of histologically confirmed diagnosis of estrogen receptor (ER) expression >10% and/or progesterone receptor (PR) expression >10% breast cancer based on local laboratory results. In case ER 10% and PR >10% the ER and PR expression need to be confirmed in a referral center. Tumor must be HER2- as defined by ASCO-CAP guidelines. If HER2 status is unavailable then testing must be performed/repeated.
3. Patients must have progressed on fulvestrant as a preceding treatment line (as first or second line therapy). In case of fulvestrant discontinuation, this discontinuation has not exceeded 12 weeks. In case fulvestrant plus a CDK4/6 inhibitor has been given in 1st line as last treatment, the patient must have progressed during or shortly (<12 months) after stopping adjuvant treatment with an (NS)AI.
4. Previous treatment with a CDK4/6 inhibitor in the advanced setting is mandatory.
5. The presence of an activating PIK3CA mutation; preferably detected in a metastasis as PIK3CA mutation status may change during the course of the disease. In case a biopsy from a metastasis is not obtainable, mutation analysis may be performed on the primary tumor or archival tumor material.
6. Evaluable disease* as defined per RECIST v.1.1 (Eisenhauer et al, 2009). Tumor lesions previously irradiated or subjected to other locoregional therapy will only be deemed measurable if disease progression at the treated site after completion of therapy is clearly documented. * Evaluable disease in this study is defined as measurable and non-measurable disease according to RECIST, with the exception of truly non-measurable disease only (i.e. ascites or pleural effusion as only site of disease). In case of truly non-measurable disease only, a patient is NOT considered evaluable according to RECIST. Bone-only disease is considered evaluable.
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2.
8. Adequate organ and marrow function defined as follows: a) ANC 1.0 x 10e9 /L; b) Platelets 75 x 10e9 / L; c) Estimated creatinine clearance 30 mL/min as calculated using the method standard for the institution; d) Total serum bilirubin ≤3x ULN (≤5x ULN if Gilbert's disease); e) ASAT and ALAT ≤3x ULN (≤5x ULN if liver metastases present)
9. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 4.03 Grade except other toxicities not considered a safety risk for the patient at investigator's discretion.
10. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
11. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study before any study-specific activity is performed.

Exclusion criteria 14

1. Patients with advanced, symptomatic, visceral spread, who are at risk of life-threatening complications in the short term (visceral crisis), e.g. patients with massive uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis, and >50% liver involvement
2. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (e.g., radiotherapy, stereotactic surgery) and are clinically stable without the use of steroids for at least 4 weeks before enrollment.
3. Prior treatment with an PI3K /AKT/mTOR inhibitor
4. Prior treatment with chemotherapy in the advanced setting.
5. (Prior) use of oral SERD in any setting
6. Type 1 diabetes or uncontrolled type 2 diabetes. Type 2 diabetes is deemed uncontrolled when the Hba1C at screening exceeds 68 mmol/mol.
7. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any upper gastrointestinal surgery including gastric resection.
8. Major surgery, any investigational agents, or other anticancer therapy within 2 weeks before enrollment.
9. Diagnosis of any other malignancy prior to enrollment, except those that are not believed to influence the prognosis and do not require any further treatment. This includes but is not limited to adequately treated basal cell or squamous cell skin cancer and carcinoma in situ of the cervix.
10. Known allergy for alpelisib or fulvestrant or previous unacceptable toxicity during treatment with fulvestrant.
11. Clinically significant, uncontrolled heart disease and/or recent cardiac events including any of the following: History of documented congestive heart failure (New York Heart Association functional classification III-IV); Clinically significant cardiac arrhythmias, (e.g., ventricular tachycardia), complete left bundle branch block, high grade AV block (e.g. bifascicular block, Mobitz type II and third degree AV block without pacemaker in place; Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or Fridericia QT correction formula (QTcF) > 470 msec at screening (mean of triplicate ECGs); Any recent cardiac events that would -in the opinion of the treating clinician- potentially intervene with study treatment.
12. Current use of any of the following medications and these medications cannot be discontinued 7 days prior to the start of the treatment: Strong CYP3A4 inducers Inhibitors of BCRP See appendix B for forbidden co-medications.
13. For women: pregnancy. For sexually active males: unwillingness to take precautions to make sure they do not inseminate.
14. Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the clinician or investigator, would make the patient inappropriate for entry into this study, include, but are not limited to: - History of severe cutaneous reactions, such as Stevens-Johnson Syndrome (SJS), Erythema Multiforme (EM), Toxic Epidermal Necrolysis (TEN), or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS); - History of pancreatitis; - Unresolved osteonecrosis of the jaw; - Severe cases of auto-immune disease; - Clinically relevant pneumonitis; - Suicidal ideations / suicidal behavior.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. To determine Progression-free survival (PFS), defined as time from study enrollment to disease progression or death from any cause, with censoring when fulvestrant and alpelisib are stopped and another treatment is initiated without confirmed disease progression.

Secondary endpoints 12

1. To determine Progression-free survival (PFS) 'on treatment' defined as time from study enrollment to disease progression or death from any cause, with censoring when fulvestrant and alpelisib are stopped earlier than disease progression
2. to determine the Objective Response Rate (CR/PR)
3. to determine the Clinical Benefit Rate (SD/CR/PR)
4. to determine the Duration of Response (DoR)
5. to evaluate safety and tolerability
6. to determine risk factors for alpelisib-induced hyperglycemia
7. to determine which management is needed in patients with alpelisib-induced hyperglycemia, and time till resolvement
8. to assess Quality of Life (QoL)
9. to evaluate Patient Reported Outcome Measures (PROMs)
10. to compare PFS in patients with the 11 most frequent activating PIK3CA mutations with PFS in patients with unselected activating PIK3CA mutations (including rare mutations)
11. to determine Overall Survival (OS)
12. to determine pharmacokinetics of alpelisib

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 9

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

BOOG Study Center B.V.

Sponsor organisation

BOOG Study Center B.V.

Address

Moreelsepark 1

City

Utrecht

Postcode

3511 EP

Country

Netherlands

Scientific contact point

Organisation

BOOG Study Center B.V.

Contact name

BOOG Study Center

Public contact point

Organisation

BOOG Study Center B.V.

Contact name

BOOG Study Center

Third parties 2

Locations

1 EU/EEA country · 25 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 4 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications