Impact of time of alpelisib administration, concomitant fasting and low carbohydrate diet on alpelisib toxicity and efficacy; a pilot randomized controlled phase IIb trial- ITACA

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Croatian Cooperative Group For Clinical Trial Research In Oncology

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2025-02-27

Transition trial

Yes

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2025-521008-22-00

EudraCT number

2021-000845-42

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Primary objective: To evaluate if there are differences in exposure
adjusted incidence rates of grade 3 or 4 hyperglycemia between treatment
with alpelisib in the evening at 22:00h with fasting period of five hours
and suggestion for low carbohydrate diet in combination with fulvestrant
compared to alpelisib administered according to EMA approved
recommendation for posology and method of administration and
fulvestrant, within the first 3 months or 30 days after the treatment
discontinuation whichever comes first in men and postmenopausal
women with HR+, HER2 negative, PIK3CA mutated metastatic breast
cancer, who progressed on previous hormone therapy

Conditions and MedDRA coding

metasatic breast cancer, hormon positive, her 2 negative

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 1. Patient is an adult male or female (≥ 18 years of age) with advanced (loco regionally recurrent not amenable to curative therapy or metastatic) hormone receptor-positive, HER2-negative breast cancer 2. Patient has documented evidence of a mutation in the PIK3CA gene as determined in tumor tissue or plasma by a local laboratory. 3. Written informed consent 4. If female, then the patient is postmenopausal. Postmenopausal status is defined either by: - Prior bilateral oophorectomy - Age ≥60 - Age <60 and amenorrhea for ≥12 months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and Follicle-stimulating Hormone (FSH) and estradiol in the postmenopausal range per local normal range 5. Patient has evidence of recurrence or progression during or after AI therapy (i.e. letrozole, anastrozole, exemestane) or AI and CDK 4/6i therapy (ribociclib, palbociclib, abemaciclib). AI therapy does not need to be the latest treatment regimen. 6. Patient has a histologically and/or cytologically confirmed diagnosis of ER+ and/or PgR+ breast cancer by local laboratory. 7. Patient has adequate bone marrow and organ function as defined by the following laboratory values: 1) Absolute neutrophil count ≥ 1.5 × 109/L 2) Platelets ≥ 100 × 109/L 3) Hemoglobin ≥ 9.0 g/dL 4) Potassium, magnesium and calcium (corrected for serum albumin) within normal limits or ≤ grade 1 according to National Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 if judged clinically not significant by the Treating Physician, or corrected with supplements 5) INR ≤ 1.5 6) Creatinine clearance > 50% LLN 7) In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN. If the patient has liver metastases, ALT and AST ≤ 5 × ULN 8) Total serum bilirubin < ULN (or ≤ 1.5 × ULN if liver metastases are present, or total bilirubin ≤ 3.0 × ULN and direct bilirubin in normal range for patients with Gilbert’s syndrome) 9) Fasting plasma glucose (FPG) ≤ 140 mg/dL (7.7 mmol/L)* and glycosylated Hemoglobin (HbA1c) ≤ 6.4% (both criteria have to be met) 10) Fasting Serum Amylase ≤ 2 × ULN 11) Fasting Serum Lipase ≤ ULN

Exclusion criteria 1

1. 1) Patient has history of hypersensitivity to any drugs or metabolites of PI3K inhibitor or any of the excipients of alpelisib. 2) Patient with established diagnosis of diabetes mellitus type I or uncontrolled type II. 3) Patient has a known history of Steven Johnson’s syndrome or toxic epidermal necrolysis. 4) Patient has a known history of Human Immunodeficiency Virus (HIV) infection. 5) Patient has had surgery within 14 days prior to starting program drug or has not recovered from major adverse reactions. 6) Patient has not recovered to grade 1 or better (except for alopecia) from related adverse reactions of prior antineoplastic therapies. 7) Patient has other prior or concurrent malignancy, with the exception of adequately treated basal or squamous cell skin cancer or other in situ cancer, or any other cancer from which the patient has been disease-free for ≥ 3 years. 8) Patient has central nervous system (CNS) involvement, except for patients fulfilling the following 3 criteria: - completed prior therapy (including radiation and/or surgery) for CNS metastases ≥ 28 days prior to the start of program treatment and - CNS tumor is clinically stable at the start of program treatment and - patient is not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases 9) Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of alpelisib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). 10) Patient who has other concurrent severe and/or uncontrolled medical conditions that would, in the Treating Physician’s judgment, contraindicate administration of alpelisib (e.g. active or uncontrolled severe infection, chronic active hepatitis, immunocompromised, acute or chronic pancreatitis, uncontrolled high blood pressure, interstitial lung disease, unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to enrolment, serious uncontrolled cardiac arrhythmia, symptomatic pericarditis, etc.). 11) Patient who is concurrently being treated with drugs known to be strong inhibitors or inducers of the isoenzyme CYP3A; switching to different medications prior to start of program treatment is allowed within the last 5 days prior to starting program treatment. 12) Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to start of program treatment, or who have not fully recovered from adverse reactions of such treatment. Note: The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular). 13) Male patient who does not apply highly effective contraception during the treatment with alpelisib and through the duration as defined below after the final dose of alpelisib. - Sexually active males should use a condom during intercourse while taking drug and for at least 4 weeks after stopping alpelisib and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Exposure-adjusted incidence rate of grade 3 or 4 hyperglycemia within the first 3 months or 30 days after the treatment discontinuation whichever comes first

Secondary endpoints 1

1. 1) Median time to the first grade 3 or 4 hyperglycemia from the first dose of study treatment until 30 days from permanent treatment discontinuation, 2) Exposure-adjusted incidence rate of any grade hyperglycemia within the first 3 months or 30 days after the treatment discontinuation whichever comes first 3) ORR from randomization to 30 days after the treatment discontinuation PFS from randomization to the end of the study 4) Exposure-adjusted incidence rate of all grade hyperglycemia,

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Croatian Cooperative Group For Clinical Trial Research In Oncology

Sponsor organisation

Croatian Cooperative Group For Clinical Trial Research In Oncology

Address

Busiceva 5

City

Split

Postcode

21000

Country

Croatia

Scientific contact point

Organisation

Croatian Cooperative Group For Clinical Trial Research In Oncology

Contact name

Eduard Vrdoljak

Public contact point

Organisation

Croatian Cooperative Group For Clinical Trial Research In Oncology

Contact name

Eduard Vrdoljak

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

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