Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Criterium, Inc.
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?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.
Is the drug Alpelisib, Tucatinib a promising treatment for breast cancer?Yes, Alpelisib, also known as Piqray, is a promising drug for breast cancer, especially for those with specific genetic mutations. It has shown effectiveness in controlling the disease in patients with PIK3CA mutations, which are common in certain types of breast cancer.12368
What safety data exists for Alpelisib and Tucatinib in breast cancer treatment?Alpelisib, approved for HR-positive, HER2-negative breast cancer, has shown efficacy but is associated with adverse events such as diarrhea, stomatitis, and hyperglycemia. Tucatinib, approved for HER2-positive breast cancer, demonstrated safety concerns like diarrhea and hepatotoxicity. Both drugs have been evaluated in clinical trials, with Alpelisib in the SOLAR-1 trial and Tucatinib in the HER2CLIMB trial, highlighting their benefit-risk profiles.235910
What data supports the idea that Alpelisib + Tucatinib for Breast Cancer is an effective drug?The available research shows that Alpelisib, when used with another drug called fulvestrant, is effective for a specific type of breast cancer that has a PIK3CA mutation. In a study, it helped control the disease in 58.2% of cases with PIK3CA-altered tumors. Another study showed that patients who had already tried many other treatments still benefited from Alpelisib, with 45.3% of them seeing positive results after six months. Tucatinib, on the other hand, has shown promise in treating brain metastases in HER2-positive breast cancer, which means it can help when cancer spreads to the brain. While there is no direct data on the combination of Alpelisib and Tucatinib, each drug has shown effectiveness in treating specific aspects of breast cancer.12347
Do I need to stop my current medications to join the trial?The trial protocol does not specify if you need to stop your current medications. However, you cannot use strong CYP3A4 or CYP2C8 inducers or inhibitors within 3 elimination half-lives before starting the study treatments. It's best to discuss your current medications with the trial team.
Eligibility Criteria
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.Inclusion Criteria
My tumor has a PIK3CA mutation.
I know my tumor's estrogen and progesterone receptor status.
My breast cancer is advanced, cannot be surgically removed, and is HER2 positive.
I am fully active or can carry out light work.
Exclusion Criteria
I cannot swallow pills or have a stomach condition affecting medication absorption.
I have been treated with alpelisib or similar drugs for over a month.
I've had more than one treatment with specific cancer drugs for my advanced cancer.
I have type 1 diabetes or my type 2 diabetes is not under control.
I have HIV with a CD4+ count below 350 cells/μL.
I haven't had a heart attack or major heart procedure in the last 6 months.
I do not have serious heart conditions like uncontrolled high blood pressure or heart failure.
I do not have active hepatitis B, hepatitis C, or HIV.
I have had acute pancreatitis in the last year or suffer from chronic pancreatitis.
I am not currently on IV treatments for infections.
Treatment Details
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.
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.
Alpelisib is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Piqray for:
- Hormone receptor-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen
🇪🇺 Approved in European Union as Piqray for:
- Hormone receptor-positive, HER2-negative, PIK3CA-mutated, locally advanced or metastatic breast cancer in combination with fulvestrant
Find a clinic near you
Research locations nearbySelect from list below to view details:
Mount Sinai Miami Cancer Research ProgramMiami, FL
Renae Cancer QualeMadison, WI
University of Wisconsin Carbone Cancer CenterMadison, WI
Louisiana State University Health Sciences CenterNew Orleans, LA
More Trial Locations
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Who is running the clinical trial?
Criterium, Inc.Lead Sponsor
Seagen Inc.Industry Sponsor
NovartisIndustry Sponsor
References
The PI3Kα Inhibitor Alpelisib Has Activity in PIK3CA-altered Tumors. [2019]The PI3Kα inhibitor alpelisib achieved a 58.2% disease control rate in PIK3CA-altered solid tumors.
Alpelisib: First Global Approval. [2020]Alpelisib (Piqray™)-an orally available phosphatidylinositol 3-kinase (PI3K) inhibitor with specific activity against PI3K alpha (PI3Kα)-is being developed by Novartis for the treatment of breast cancer. Alpelisib has demonstrated efficacy in combination with fulvestrant as treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer in patients with a PIK3CA mutation and was recently approved for this indication in the USA. This article summarizes the milestones in the development of alpelisib leading to this first approval.
Pharmaceutical Approval Update. [2020]Alpelisib (Piqray) for HR-positive/HER2-negative, PIK3CA-mutated, advanced/ metastatic breast cancer; polatuzumab vedotin-piiq (Polivy) for diffuse large B-cell lymphoma; and eculizumab (Soliris) for neuromyelitis optica spectrum disorder.
Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases. [2021]Brain metastases are frequent in HER2-positive breast cancer. ONT-380 (tucatinib) is a potent selective inhibitor of HER2 with intracranial activity in preclinical models.
FDA Approval Summary: Tucatinib for the Treatment of Patients with Advanced or Metastatic HER2-positive Breast Cancer. [2022]On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. This was the first new molecular entity evaluated under Project Orbis, an FDA Oncology Center of Excellence initiative, which supports concurrent review of oncology drugs by multiple global health authorities. Approval was based on the HER2CLIMB trial, which randomized patients to receive tucatinib or placebo with trastuzumab and capecitabine. Tucatinib demonstrated efficacy compared with placebo in progression-free survival [PFS; HR: 0.54; 95% confidence interval (CI): 0.42-0.71; P < 0.00001] and overall survival (OS; HR: 0.66; 95% CI, 0.50-0.87; P = 0.00480). Patients with either treated and stable or active brain metastases made up 48% of the study population. PFS in patients with brain metastases confirmed benefit (HR: 0.48; 95% CI, 0.34-0.69; P < 0.00001). The benefit in patients with brain metastases allowed for inclusion of this specific population in the indication. Important safety signals included diarrhea and hepatotoxicity which are listed under Warnings and Precautions. This article summarizes the FDA thought process and data supporting the favorable benefit-risk profile and approval of tucatinib.
Combined PIK3CA and FGFR Inhibition With Alpelisib and Infigratinib in Patients With PIK3CA-Mutant Solid Tumors, With or Without FGFR Alterations. [2022]Concurrent PIK3CA mutations and fibroblast growth factor receptor (FGFR) alterations occur in multiple cancer types, including estrogen receptor-positive breast cancer, bladder cancer, and endometrial cancer. In this first-in-human combination trial, we explored safety and preliminary efficacy of combining the PI3Kα selective inhibitor alpelisib with the FGFR1-4 selective inhibitor infigratinib.
Alpelisib and fulvestrant in PIK3CA-mutated hormone receptor-positive HER2-negative advanced breast cancer included in the French early access program. [2023]SOLAR-1 and BYLieve trials documented the efficacy of the PI3K-inhibitor alpelisib in pre-treated PIK3CA-mutant, hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC) patients. We report here real-life data of patients prospectively registered in the French alpelisib early access program (EAP) opened to PIK3CA-mutant HR+/HER2- ABC patients treated with alpelisib and fulvestrant. Primary endpoint was PFS by local investigators using RECIST1.1. Eleven centers provided individual data on 233 consecutive patients. Patients had received a median number of 4 (range: 1-16) prior systemic treatments for ABC, including CDK4/6 inhibitor, chemotherapy, fulvestrant and everolimus in 227 (97.4%), 180 (77.3%), 175 (75.1%) and 131 (56.2%) patients, respectively. After a median follow-up of 7.1 months and 168 events, median PFS was 5.3 months (95% CI: 4.7-6.0). Among 186 evaluable patients, CBR at 6 months was 45.3% (95% CI: 37.8-52.8). In multivariable analysis, characteristics significantly associated with a shorter PFS were age 5 lines of prior treatments (HR = 1.4, 95% CI = 1.0-2.0) and the C420R PI3KCA mutation (HR = 4.1, 95% CI = 1.3-13.6). N = 91 (39.1%) patients discontinued alpelisib due to adverse events. To our knowledge, this is the largest real-life assessment of alpelisib efficacy. Despite heavy pre-treatments, patients derived a clinically relevant benefit from alpelisib and fulvestrant.
Alpelisib Efficacy without Cherry-PI3King Mutations. [2023]The PI3K inhibitor alpelisib is clinically approved for the treatment of metastatic estrogen receptor-positive breast cancers harboring hotspot mutations in PIK3CA, which encodes a subunit of PI3K. Prospective clinical trial results demonstrated benefit from alpelisib for the treatment of advanced ER+ breast cancers harboring PIK3CA mutations in the hotspots of exons 7, 9, and 20. However, 20% of PIK3CA mutations occur in non-hotspot regions. A recent article demonstrated that patients with cancers bearing non-hotspot PIK3CA mutations also derived benefit from alpelisib, which will inform clinical decision-making moving forward. See related article by Rugo et al., p. 1056.
FDA Approval Summary: Alpelisib for PIK3CA-related Overgrowth Spectrum (PROS). [2023]On April 5, 2022, FDA granted accelerated approval to alpelisib for the treatment of adult and pediatric patients two years of age and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy. Efficacy was evaluated using real-world data (RWD) from EPIK-P1 (NCT04285723), a single-arm clinical study in patients two years of age and older with severe or life-threatening PROS who received alpelisib as part of an expanded access program (EAP) for compassionate use. The primary endpoint was confirmed radiological response rate at Week 24 as determined by blinded independent central review (BICR), using volumetric-based criteria given the atypical growth pattern and irregular shape of PROS lesions. Radiological response was defined as a ≥20% reduction from baseline in the sum of measurable target lesion volume in up to three lesions. Of the 37 patients in the efficacy population, 27% (95% CI: 14, 44) had a radiological response at Week 24. Duration of response (DOR) was an additional efficacy outcome measure, and among responders, 60% had a response lasting ≥12 months. Further, supportive clinical documentation suggested early signals of clinical benefit (i.e., improvement in PROS-related signs and symptoms). The most common (≥10%) adverse reactions were diarrhea, stomatitis and hyperglycemia.
A Cohort Study of the Antitumor Efficacy and Toxicity Profile of Alpelisib for Metastatic or Locally Advanced HR+, HER2- Breast Cancer: A Single-Institution Experience. [2023]Alpelisib is approved in combination with endocrine therapy (ET) to treat patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) progressive metastatic breast cancer (MBC). The SOLAR-1 trial demonstrated the efficacy of this oral agent and showed that, while alpelisib improves outcomes compared to placebo, it is also associated with clinically relevant adverse events (AEs). There is a pressing need for improved knowledge on the effectiveness and tolerability of this agent in real-world patient populations.