Rash & Diarrhea Prophylaxis With Capivasertib (SAFE-CAP)

A Phase II Trial to Improve Safety of Capivasertib for HR+/HER2- Metastatic Breast Cancer

This is a randomized, multicenter, phase II clinical trial evaluating prophylactic strategies to mitigate common toxicities associated with capivasertib in combination with fulvestrant in participants with hormone receptor-positive (HR+), HER2-negative advanced breast cancer who are eligible for this treatment regimen.

Study Overview

• Status: Not yet recruiting
• Conditions: Metastatic HR+/HER2- Breast Cancer
• Intervention / Treatment: Drug: Capivasertib; Drug: Loperamide; Drug: Fulvestrant; Drug: Ceterizine

Detailed Description

Capivasertib is an important treatment option for patients with metastatic hormone receptor-positive breast cancer. Understanding how to decrease the incidence of adverse events will allow patients to stay on the medication longer, potentially deriving greater benefit, and may ultimately result in improved time to next treatment. The investigators hypothesize that cutaneous and diarrheal prophylaxis with antihistamine and loperamide for patients initiating capivasertib will reduce the incidence of grade 2 or greater rash and/or diarrhea at eight weeks.

• Study Type: Interventional
• Enrollment (Estimated): 108
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Laura Kane; Phone Number: 773-369-6904; Email: laura.kane@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University
      • Principal Investigator: Maryam Lustberg, MD
      • Contact: Carl Brown; Phone Number: 475-241-1065; Email: carl.brown@yale.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the clinical study protocol.
2. Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses.
3. Participants must be aged ≥18 years at the time of signing the ICF.

4. Adult females, pre- and/or post-menopausal, and adult males:

   - Pre-menopausal (and peri-menopausal i.e., those that do not meet the criteria for post-menopausal defined below) women can be enrolled if amenable to treatment with an LHRH agonist. Participants are to have commenced concomitant treatment with LHRH agonist at least four weeks prior to Cycle 1, Day 1 and must be willing to continue it for the duration of the study.

   Post-menopausal women are defined as:

   • Aged ≥60 years of age, OR
   • Aged <60 years of age and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments/chemotherapy/ovarian suppression/tamoxifen or similar. These participants should also have serum estradiol and follicle stimulating hormone (FSH) levels confirmed as being within the standard laboratory reference range for post-menopausal females, OR
   • Documented irreversible bilateral oophorectomy.
5. Metastatic or locally advanced disease with radiological or objective evidence of recurrence or progression; locally advanced disease must not be amenable to resection with curative intent.
6. Participants with metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations, as confirmed by local or central testing of tumor tissue and/or circulating tumor DNA (ctDNA).
7. Participants eligible for treatment with capivasertib and fulvestrant for metastatic breast cancer.
8. ECOG performance status 0 or 1 with no deterioration over the previous 2 weeks and life expectancy of ≥12 weeks.
9. Adequate hematologic, coagulation, hepatic, and renal parameters.
10. Participants must be able to swallow and retain oral medication.

11. Participants must adhere to the following reproductive and contraceptive requirements:

    a. For participants of childbearing potential (POCBP): i. Participant of childbearing potential is defined as an individual who is premenopausal and capable of becoming pregnant, including those using contraception, those who are single, or those with partners who have had a vasectomy.

ii. Participants must not be pregnant or breastfeeding. iii. A negative serum pregnancy test must be obtained at screening within 72 hours before the first dose of the study treatment, and participants must agree to further pregnancy tests throughout the study, if required.

iv. Participants must use at least one highly effective method of contraception combined with a barrier method while on study treatment and for 1 years after the last dose of the study drug.

v. Participants must not donate or freeze eggs for future use related to assisted reproduction while on study treatment and for 1 month after the last dose of the study drug.

b. For participants with partners of childbearing potential: i. If a participant has a partner who could become pregnant, that partner must use a highly effective method of contraception combined with a barrier method while the participant is on study treatment and for 16 weeks after the last dose of the study drug, unless the participant is vasectomized.

ii. Participants must not donate or freeze sperm for future use related to assisted reproduction while on study treatment and for 4 months after the last dose of the study drug.

c. Highly effective methods of contraception include: i. Combined hormonal contraception (estrogen and progestogen) that inhibits ovulation (oral, intravaginal, or transdermal).

ii. Progestogen-only hormonal contraception that inhibits ovulation (oral, injectable, or implantable).

iii. Intrauterine device (IUD). iv. Intrauterine hormone-releasing system. v. Bilateral tubal occlusion. vi. Sexual abstinence (the reliability of abstinence must be evaluated concerning the duration of the clinical study and the participant's lifestyle).

vii. A vasectomized partner (provided the partner is the sole sexual partner of the POCBP study participant and that the vasectomized partner has received medical confirmation of the surgical success).

d. Barrier methods are not considered highly effective and should not be used alone to meet study contraceptive requirements. However, they may be used in addition to a highly effective method for extra protection. These include: i. Male condom. ii. Female condom. iii. Cervical cap. iv. Diaphragm with spermicide. v. Contraceptive sponge with spermicide

Exclusion Criteria:

1. A disease burden that makes the participant ineligible for endocrine therapy per the investigator's best judgment (e.g., symptomatic visceral disease that is potentially life-threatening in the short-term)
2. Malignancies other than breast cancer within five years prior to study treatment initiation (except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma or Stage I endometrioid uterine cancer).
3. With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment.
4. Known abnormalities in coagulation such as bleeding diathesis, or treatment anticoagulants precluding intramuscular injections of fulvestrant or LHRH, if applicable.
5. Prior exposure to any chemotherapy or anti-cancer agents other than those specified in the protocol (e.g. hormonal therapy such as LHRH agonists) without appropriate washout period before randomization/enrollment, for example, randomization within 3 half-lives of a small molecule anti-cancer agent, or within 4 weeks for any antibody-based anticancer agents.
6. Concurrent use of herbal or natural products intended as treatment or prophylaxis for any type of cancer.
7. Radiotherapy within 2 weeks prior to the first dose of study intervention
8. Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.
9. Strong inhibitors of CYP3A4 or strong/moderate inducers of CYP3A4 within 2 weeks prior to the first dose of capivasertib (3 weeks for St John's wort), Note that adequate washout or dose reduction may be required for some CYP3A substrates with a narrow therapeutic window prior to initiating capivasertib dosing.
10. Any concomitant medication that may interfere with fulvestrant, cetirizine, and loperamide safety and efficacy based on the prescribing information of fulvestrant, cetirizine, and loperamide and local clinical guidelines.

11. Clinically significant abnormalities of glucose metabolism as defined by any of the following:

    1. Participants with diabetes mellitus type 1 or diabetes mellitus type 2 requiring insulin treatment.
    2. HbA1c ≥8.0% (63.9 mmol/mol).
12. Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids within four weeks prior to study treatment initiation.
13. Leptomeningeal metastases.

14. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

    1. Absolute neutrophil count <1.5 × 109 /L.
    2. Platelet count <100 × 109 /L.
    3. Hemoglobin <9 g/dL (<5.59 mmol/L). NOTE: any blood transfusion must be >14 days prior to the determination of a haemoglobin ≥9 g/dL (≥5.59 mmol/L).
    4. Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) >2.5 times upper limit of normal (ULN) if no demonstrable liver metastases or >5 × ULN in the presence of liver metastases.
    5. Total bilirubin >1.5 × ULN (participants with confirmed Gilbert's syndrome may be included in the study).
    6. Creatinine >1.5 × ULN concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is >1.5 × ULN.
15. As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Participants with HIV that is controlled (not detectable viral load) with highly active antiretroviral therapy (HAART) are eligible to participate. Screening for chronic conditions is not required.
16. Prior treatment with AKT or PI3K inhibitors.
17. History of skin or gastrointestinal disorders that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of capivasertib.
18. History of hypersensitivity to active or inactive excipients of capivasertib, fulvestrant and LHRH agonists (if applicable, i.e., concomitant LHRH agonist required in this study) or drugs with a similar chemical structure or class to capivasertib, fulvestrant or LHRH agonists (if applicable, i.e., concomitant LHRH agonist required in this study).
19. History of intolerability to cetirizine or loperamide.
20. Refractory nausea and vomiting, malabsorption syndrome, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection, or other condition that would preclude adequate absorption of capivasertib.
21. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
22. Evidence of dementia altered mental status or any psychiatric condition that would prohibit understanding or rendering of informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rash and diarrhea prophylaxis; All participants will receive capivasertib + fulvestrant. Capivasertib will be administered at 400 mg orally, twice daily (BID), on 4-days-on/3-days-off schedule. Fulvestrant will be administered at 500 mg intramuscularly (IM) every 14 days for the first three injections, and every 28 days thereafter. Participants in this arm will take cetirizine 10 mg orally once daily, and loperamide 2 mg orally once daily on capivasertib dosing days, starting on Cycle 1 Day 1 and continued for the first eight weeks (each cycle = 28 days).	Drug: Capivasertib; 400 mg orally, twice daily (BID), on 4-days-on/3-days-off schedule.; Drug: Loperamide; 2 mg orally once daily on capivasertib dosing days; Drug: Fulvestrant; 500 mg Administered intramuscularly every 14 days for the first three injections and every 28 days thereafter.; Drug: Ceterizine; 10 mg orally once a day, starting on Cycle 1 Day 1 and continued for the first eight weeks (each cycle=28 days)
Experimental: Rash prophylaxis; All participants will receive capivasertib + fulvestrant. Capivasertib will be administered at 400 mg orally, twice daily (BID), on 4-days-on/3-days-off schedule. Fulvestrant will be administered at 500 mg intramuscularly (IM) every 14 days for the first three injections, and every 28 days thereafter. Participants will take cetirizine 10 mg orally once daily, starting on Cycle 1 Day 1 and continued for the first eight weeks (each cycle = 28 days).	Drug: Capivasertib; 400 mg orally, twice daily (BID), on 4-days-on/3-days-off schedule.; Drug: Fulvestrant; 500 mg Administered intramuscularly every 14 days for the first three injections and every 28 days thereafter.; Drug: Ceterizine; 10 mg orally once a day, starting on Cycle 1 Day 1 and continued for the first eight weeks (each cycle=28 days)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients who experience grade 2 or greater diarrhea as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0	The study aims to evaluate the effectiveness of prophylactic strategies to mitigate diarrhea in patients receiving capivasertib in combination with fulvestrant for hormone receptor-positive (HR+), HER2-negative advanced breast cancer. Toxicities will be graded on the following scale: grade 1 mild, grade 2 moderate, grade 3 severe, grade 4 life threatening/disabling and grade 5 death related to AE.	At the eight-week mark from the commencement of the capivasertib treatment in the study
Number of patients who experience grade 2 or greater rash as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0	The study aims to evaluate the effectiveness of prophylactic strategies to mitigate rash in patients receiving capivasertib in combination with fulvestrant for hormone receptor-positive (HR+), HER2-negative advanced breast cancer. Toxicities will be graded on the following scale: grade 1 mild, grade 2 moderate, grade 3 severe, grade 4 life threatening/disabling and grade 5 death related to AE	At the eight-week mark from the commencement of the capivasertib treatment in the study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Duration of Capivasertib Treatment from Initial to Final Dose	This secondary outcome measure aims to calculate the average duration of time that patients with metastatic HR+/HER2- breast cancer remain on capivasertib treatment. This measure will be determined by recording the interval between the first administered dose and the last dose of capivasertib received by each patient. The results will provide valuable information on the typical length of time that patients can maintain the capivasertib regimen.	From the start of treatment to the end of the treatment period, assessed up to 24 months
Rates of Hyperglycemia in patients with metastatic HR+/HER2- breast cancer	The assessment will capture the frequency and severity of hyperglycemic events during the treatment period. Participants will self-monitor and record their fasting blood glucose then share with their treating physician, in real time	From the start of treatment to the end of the treatment period, assessed up to 24 months
Average Number of Completed Cycles of Capivasertib Treatment	This secondary outcome measure aims to quantify the number of completed treatment cycles of capivasertib among patients with metastatic HR+/HER2- breast cancer. Each completed cycle is defined as a full course of capivasertib as per the prescribed treatment protocol. Data will be collected to assess the completion rate of these cycles, offering insights into patient persistence with the treatment regimen and any factors influencing cycle completion.	From the start of treatment to the end of the treatment period, assessed up to 24 months
Rate of Adherence to Capivasertib in Patients with Metastatic HR+/HER2- Breast Cancer	This secondary outcome measure aims to evaluate patient adherence to the prescribed capivasertib treatment regimen among individuals diagnosed with metastatic HR+/HER2- breast cancer. Adherence will be monitored by examining drug continuation, interruption, and dose reductions through a comprehensive review of drug accountability records.	From the start of treatment to the end of the treatment period, assessed up to 24 months.
Quality of Life as Measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)	This measure will assess the overall quality of life and functioning of patients based on the EORTC QLQ-C30 instrument. The questionnaire includes scales for physical, role, cognitive, emotional, and social functioning, as well as global health status. Scores range from 0 to 100 with higher scores indicating better quality of life or functioning.	At baseline, every 4 weeks during treatment, and every 12 weeks during follow-up, up to 24 months
Diarrhea Severity as Measured by Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)	This sub-measure will assess the severity and impact of diarrhea as reported by patients using the PRO-CTCAE instrument. Scores range from 0 (no symptoms) to 4 (severe symptoms), with higher scores indicating worse outcomes	At baseline, every 4 weeks during treatment, and every 12 weeks during follow-up, up to 24 months
Rash Severity as Measured by Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)	This sub-measure will assess the severity and impact of rash as reported by patients using the PRO-CTCAE instrument. Scores range from 0 (no symptoms) to 4 (severe symptoms), with higher scores indicating worse outcomes.	At baseline, every 4 weeks during treatment, and every 12 weeks during follow-up, up to 24 months
Fatigue Severity as Measured by Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)	This sub-measure will assess the severity and impact of fatigue as reported by patients using the PRO-CTCAE instrument. Scores range from 0 (no symptoms) to 4 (severe symptoms), with higher scores indicating worse outcomes.	At baseline, every 4 weeks during treatment, and every 12 weeks during follow-up, up to 24 months

Collaborators and Investigators

• Sponsor: Maryam Lustberg
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Maryam Lustberg, MD, Yale University

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2029

Study Registration Dates

• First Submitted: February 9, 2026
• First Submitted That Met QC Criteria: February 16, 2026
• First Posted (Actual): February 23, 2026

Study Record Updates

• Last Update Posted (Actual): February 24, 2026
• Last Update Submitted That Met QC Criteria: February 20, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Diarrhea; Rash; Capivasertib
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Skin Diseases; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Signs and Symptoms; Diarrhea; Exanthema; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Polycyclic Compounds; Piperidines; Steroids; Fused-Ring Compounds; Estradiol; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Fulvestrant; Loperamide; capivasertib; ceterizine hydrochloride
• Other Study ID Numbers: 2000037614

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes