What side effects are associated with this type of intervention?

Common treatments for breast cancer, particularly those similar to Alpelisib (a PI3K inhibitor) and Tucatinib (a HER2 inhibitor), have specific side effects. PI3K inhibitors like Alpelisib are known to cause hyperglycemia, rash, diarrhea, and liver function abnormalities. HER2 inhibitors such as Tucatinib can lead to diarrhea, liver toxicity, and fatigue. Additionally, endocrine therapies like aromatase inhibitors and tamoxifen, often used in hormone receptor-positive breast cancer, can result in alopecia, bone density loss, and cardiovascular risks.

What prior FDA approvals exist?

The FDA has approved Alpelisib, a PI3K inhibitor, for use with fulvestrant in treating hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer. Tucatinib, a HER2 inhibitor, is approved in combination with capecitabine and trastuzumab for HER2-positive metastatic breast cancer. These approvals highlight targeted therapies aimed at specific genetic mutations and pathways involved in breast cancer progression.

What other types of research exist?

Promising novel alternatives for breast cancer treatment in 2024 include Trastuzumab Deruxtecan (a HER2-targeted antibody-drug conjugate) and Sacituzumab Govitecan (a Trop-2-directed antibody-drug conjugate). Both have shown significant efficacy in clinical trials for HER2-positive and triple-negative breast cancer, respectively.

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PI3K Inhibitor

Alpelisib + Tucatinib for Breast Cancer

Phase 1 & 2

Recruiting

Led By Elena Shagisultanova, MD

Research Sponsored by Criterium, Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Documented presence of activating mutation in PIK3CA in the tumor

Known ER and PR status of the tumor

Must not have

Inability to swallow pills or any significant gastrointestinal disease which would preclude the adequate oral absorption of medications

Previous treatment with alpelisib or other PI3K, mTOR or AKT inhibitor of more than 30 days duration

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 20 months

Awards & highlights

Summary

This trial tests a combination of two drugs, tucatinib and alpelisib, in patients with a specific type of advanced breast cancer. These patients have a genetic mutation and a type of cancer that may not respond well to standard treatments. The drugs work by blocking signals that help cancer cells grow. Alpelisib is approved for treating certain types of advanced breast cancer.

Who is the study for?

This trial is for adults with HER2-positive metastatic breast cancer that has a specific mutation (PIK3CA). Participants must understand the study and be willing to follow its procedures. They should have an ECOG performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. People with severe medical conditions, recent anti-cancer therapy, pregnancy, certain drug hypersensitivities, or inability to swallow pills cannot join.

What is being tested?

The trial is testing the combination of Alpelisib and Tucatinib with Fulvestrant in patients who have PIK3CA-Mutant HER2+ metastatic breast cancer. It's designed to see how safe this combo is and how well it works compared to standard treatments.

What are the potential side effects?

Alpelisib may cause high blood sugar levels, rash, nausea, fatigue and diarrhea. Tucatinib can lead to diarrhea as well as liver issues and mouth sores. Fulvestrant might result in injection site pain, weakness or bone pain.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My tumor has a PIK3CA mutation.

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I know my tumor's estrogen and progesterone receptor status.

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My breast cancer is advanced, cannot be surgically removed, and is HER2 positive.

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I am fully active or can carry out light work.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I cannot swallow pills or have a stomach condition affecting medication absorption.

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I have been treated with alpelisib or similar drugs for over a month.

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I've had more than one treatment with specific cancer drugs for my advanced cancer.

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I have type 1 diabetes or my type 2 diabetes is not under control.

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I have HIV with a CD4+ count below 350 cells/μL.

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I haven't had a heart attack or major heart procedure in the last 6 months.

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I do not have serious heart conditions like uncontrolled high blood pressure or heart failure.

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I do not have active hepatitis B, hepatitis C, or HIV.

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I have had acute pancreatitis in the last year or suffer from chronic pancreatitis.

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I am not currently on IV treatments for infections.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 20 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~20 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and 20 months for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Phase II Efficacy of tucatinib combination evaluated by progression free survival (PFS)

Phase Ib Safety and Tolerability of alpelisib and tucatinib combination, summary of all AEs and SAEs on study as evaluated by NCI-CTCAE v 5.0

Secondary study objectives

Phase II Duration of Reponse (DOR)

Phase II Incidence, nature and severity of all AEs that occur on or after C1D1 of therapy

Phase II Tumor response evaluation

+3 more

Side effects data

From 2023 Phase 2 trial • 117 Patients • NCT03043313

64%

Diarrhoea

43%

Fatigue

34%

Nausea

21%

Infusion related reaction

20%

Pyrexia

19%

Chills

19%

Decreased appetite

19%

Dermatitis acneiform

17%

Hypertension

16%

Arthralgia

16%

Vomiting

16%

Back pain

16%

Cough

14%

Constipation

14%

Abdominal pain

14%

Dyspnoea

13%

Myalgia

10%

Anaemia

10%

Anxiety

Headache

Pain in extremity

Dry skin

Pruritus

Peripheral sensory neuropathy

Insomnia

Rash maculo-papular

Influenza like illness

Dehydration

Oedema peripheral

Nasal congestion

Upper-airway cough syndrome

Productive cough

Weight decreased

Muscle spasms

Epistaxis

Hypokalaemia

Rhinitis allergic

COVID-19

Alanine aminotransferase increased

Aspartate aminotransferase increased

Dizziness

Abdominal pain upper

Dry mouth

Ejection fraction decreased

Musculoskeletal chest pain

Nephrolithiasis

Oropharyngeal pain

Rash

Haematuria

Urinary tract infection

Dysgeusia

Flank pain

Gastrooesophageal reflux disease

Dyspepsia

Large intestinal obstruction

Flatulence

Asthenia

Dysuria

Vision Blurred

Non-cardiac chest pain

Fall

Blood creatinine increased

Pollakiuria

Small intestinal obstruction

Hyponatraemia

Rhinorrhoea

Wheezing

Hypercreatinaemia

Onychomadesis

Gastrointestinal pain

Blepharospasm

Abdominal discomfort

Pelvic pain

Abdominal distension

Thrombocytopenia

Rectal haemorrhage

Peripheral swelling

COVID-19 pneumonia

Herpes zoster

Influenza

Nail infection

Rhinitis

Blood alkaline phosphatase increased

Rectal perforation

Muscular weakness

Weight increased

Dysphonia

Erythema

Nail disorder

Urticaria

Hypoalbuminaemia

Dyspnoea exertional

Pulmonary embolism

Sinus pain

Bile duct stone

Cholangitis

Sepsis

Cancer pain

Acute kidney injury

Hypotension

Angina unstable

Colitis

Gastrointestinal obstruction

Kidney infection

Renal colic

Acute respiratory failure

100%

80%

60%

40%

20%

Study treatment Arm

Tucatinib+Trastuzumab (Cohorts A+B)

Cohort C (Pre-Crossover)

Cohort C (Post-Crossover)

Trial Design

1Treatment groups

Experimental Treatment

Group I: Ib Safety Cohort /II Expansion CohortExperimental Treatment3 Interventions

In phase Ib, the tolerability of tucatinib and alpelisib combination will be confirmed and maximum tolerated dose determined. Therapy will be administered in 28 day cycles of tucatinib 300 mg PO BID and alpelisib 250 mg PO daily (dose level 1). Treatment will continue until unacceptable toxicity, disease progression, withdrawal of consent, or study closure. Fulvestrant will also be administered in patients with HR+/HER2+ metastatic breast cancer. Once RP2D is determined, the study will be continued to phase II, and new patients will enroll at RP2D. All patients in phase IB part, who are remaining on study at the time of initiation of phase II, will be rolled over to phase II. At that time, their study drug doses will be modified as follows: (1) if a patient is on the drug doses lower than RP2D, doses will not be increased; (2) if a patient is on a higher doses compared to RP2D, doses of study drugs will be changed to RP2D.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Alpelisib

2018

Completed Phase 3

~960

Tucatinib

2017

Completed Phase 2

~520

Fulvestrant

2011

Completed Phase 3

~3890

0 / 14Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Alpelisib is a PI3K inhibitor that targets the PI3K pathway, which is crucial for cell growth and survival, especially in breast cancers with PIK3CA mutations. Tucatinib is a HER2 inhibitor that targets the HER2 receptor, a protein that promotes cancer cell growth. These targeted therapies are important for breast cancer patients because they offer more effective and personalized treatment options by directly interfering with the specific molecular pathways that drive cancer progression. This can lead to better outcomes and potentially fewer side effects compared to traditional chemotherapy.

Breast Cancer Resistance to Cyclin-Dependent Kinases 4/6 Inhibitors: Intricacy of the Molecular Mechanisms.Targeting triple-negative breast cancer: optimising therapeutic outcomes.