Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

All Drugs and Chemicals

Antineoplastic Agents

Reproductive Control Agents

Hormones

Fulvestrant

Leuprolide

Goserelin

Triptorelin Pamoate

Antineoplastic Agents, Hormonal

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormone Antagonists

Oral alpelisib (300 mg daily, in 28-day cycle) and fulvestrant as per standard practice. Moreover, men and premenopausal women will receive an LH-RH analogue (goserelin, leuprorelin, or triptorelin) every 28 days ±3 days, as per standard practice

Oral ribociclib (600 mg daily, 3 weeks on, then 1 week off treatment in 28-day cycles) and fulvestrant as per standard practice. Moreover, men and premenopausal women will receive an LH-RH analogue (goserelin, leuprorelin, or triptorelin) every 28 days ±3 days, as per standard practice.

Alpelisib 300 mg once daily + fulvestrant 500 mg every 28 days

Alpelisib

Ribocilcib 600 mg once daily 3 weeks on/1 week off + fulvestrant 500 mg every 28 days

Ribociclib

Fabrice ANDRE

François LEGRAND

Aurélie MOREIRA, Dr

Khadija KALAI, Dr

Adina MARTI, Dr

Bertrand BILLEMONT, Dr

Hanifa AMMARGUELLAT, Dr

Olivier ARSENE, Dr

Monica ARNEDOS, Dr

Abeer NAJEM, Dr

Laura DEIANA, Dr

Brigitte LUCAS, Dr

George EMILE, Dr

Rolande NGUEFACK, Dr

Thomas COLLOT, Dr

Victor SIMMET, Dr

Lionel MOREAU, Dr

Xavier DURANDO, Pr

Mansour RASTKHAH, Dr

Jean-François PAITEL, Dr

Elise BONNET, Dr

Céline BIHAN, Dr

Sophie BARTHIER, Dr

Dominique GENET, Dr

Thomas BACHELOT, Dr

Olfa DERBEL MILED, Dr

Yann MOLIN, Dr

Anthony GONCALVES, Pr

William JACOT, Pr

Laurene GAVOILLE, Dr

Jean-Michel VANNETZEL, Dr

Caroline BAILLEUX, Dr

Luis TEIXEIRA, Pr

Catherine DELBALDO, Dr

Kévin BOURCIER, Dr

Jérôme MARTIN-BABAU, Dr

Pauline SOIBINET-OUDOT, Dr

Fanny LE DU, Dr

Romuald LE SCODAN, Dr

Youssef TAZI, Dr

Fanny POMMERET, Dr

Florence DALENC, Dr

Vincent MASSARD, Dr

Joana MOURATO-RIBEIRO, Dr

After an initial screening phase (SAFIR 03 - SCREENING) to identify patients with blood circulating mutated-PIK3CA tumours persistent, patients will be enrolled in the treatment phase of SAFIR 03 (SAFIR 03 - ARRIBA) that was designed as a randomised, open-label, multicentre, phase II study, for comparison of alpelisib to ribociclib in combination with fulvestrant (as the continuation of the CDK4/6 inhibitor-fulvestrant strategy) in terms of progression-free survival (PFS).

INDICATION The population eligible to the screening phase is composed of all women or men with HR+, HER2- metastatic breast cancer who are eligible for first-line treatment with a cyclin-dependent kinases (CDK) 4/6 inhibitor combined with fulvestrant (and a luteinizing hormone realeasing hormone (LH-RH) analogue in men and premenopausal women) in the context of the standard healthcare management. The screening will identify patients with high risk of relapse on any CDK4/6 inhibitor thanks to ctDNA kinetic between baseline and 4 weeks of treatment. The purpose is to early adapt the therapeutic intervention for ctDNA no drop patient to prevent from relapse. This study will propose an intervention for PIK3CA mutated patients with alpelisib vs. ribociclib. Other therapeutic approaches might be proposed to patients with wild type PIK3CA through other protocols.

The randomised study phase will include patients with persistent mutations on exons 4, 9 or 20\* of PIK3CA ctDNA after 4 weeks of treatment with any CDK4/6 inhibitor-fulvestrant in first-line setting.

After an initial screening phase (SAFIR 03 - SCREENING) to identify patients with blood circulating mutated-PIK3CA tumours persistent, patients will be enrolled in the treatment phase of SAFIR 03 (SAFIR 03 - ARRIBA) that was designed as a randomised, open-label, multicentre, phase II study, for comparison of alpelisib to ribociclib in combination with fulvestrant (as the continuation of the CDK4/6 inhibitor-fulvestrant strategy)

Detection of Tumor DNA in the Blood of Patients Receiving Standard Therapy for Hormone Receptor-positive (HR+) Non-HER2 Expressing (HER2-) Metastatic Breast Cancer as a Tool to Select Those Who May Benefit From the Next Course of Fulvestrant in Combination With Alpelisib or Ribociclib

A ctDNA Screening Program in Patients With HR+, HER2- Metastatic Breast Cancer for Detection of High-risk Relapse Patients on Any CDK4/6 Inhibitor and a Randomised Phase II Study Comparing Alpelisib Combined With Fulvestrant to Ribociclib Combined With Fulvestrant, in Patients With Persistent Targetable PIK3CA Mutations

The PFS is the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse.

Overall survival (OS) is the length of time from randomization that patients enrolled in the study are still alive.

Objective response rate (ORR) is the percentage of patients with a best response during treatment being either complete response (CR) or partial response (PR).

Duration of response (DoR) is defined as the time interval from the date of first documented CR or PR to the date of first documented disease progression or death, from any cause.

Clinical benefit rate (CBR) is defined as the proportion of patients with a best overall response of CR, PR, or stable disease during treatment.

Time to response (TTR) is defined, for subjects with an objective response (OR), as the time from randomisation to the first documentation of OR which is subsequently confirmed.

For this outcome, PFS is defined as the time interval between the date of initiation of standard of care to the date of the first documented disease progression or death, whatever the cause.

The National Cancer Institute-Common Terminology Criteria for Adverse Events version 5 (NCI-CTCAE v5) is widely accepted in the community of oncology research as the leading rating scale for adverse events. This scale, divided into 5 grades (1 = "mild", 2 = "moderate", 3 = "severe", 4 = "life-threatening", and 5 = "death") determined by the investigator, will make it possible to assess the severity of the disorders.

For non-randomised patients, OS is the length of time from the date of initiation of standard of care that patients enrolled in the study are still alive.

For non-randomised patients, PFS is the length of time during and after the treatment of a disease with the standard of care that a patient lives with the disease but it does not get worse.

Novartis

Breast Cancer Research Foundation

UNICANCER

Capecitabine

Trastuzumab

Vinorelbine

Antimetabolites

Antineoplastic Agents, Immunological

Tubulin Modulators

Antimitotic Agents

Trastuzumab either intravenous (IV) or subcutaneous (SC): 6 mg/kg IV every 3 weeks (3-weekly schedule), or 2 mg/kg IV weekly (weekly schedule)\*, or 600 mg SC every 3 weeks.

Alpelisib 300 mg oral once daily.

\*If using trastuzumab IV, a loading dose of 8 mg/kg (for the 3-weekly schedule), or 4 mg/kg (for the weekly schedule) is necessary if more than 6 weeks have passed since the previous trastuzumab dose.

Trastuzumab either intravenous (IV) or subcutaneous (SC): 6 mg/kg IV every 3 weeks (3-weekly schedule), or 2 mg/kg IV weekly (weekly schedule)\*, or 600 mg SC every 3 weeks.

Alpelisib 300 mg oral once daily.

Fulvestrant 500 mg intramuscular every 4 weeks plus loading dose on day 15 cycle 1.

Males and females who are not post-menopausal must have been on a gonadotropin-releasing hormone (GnRH) agonist (e.g. goserelin or leuprorelin) for at least 28 days prior to starting study treatment, and should continue with this therapy.

\*If using trastuzumab IV, a loading dose of 8 mg/kg (for the 3-weekly schedule), or 4 mg/kg (for the weekly schedule) is necessary if more than 6 weeks have passed since the previous trastuzumab dose.

Trastuzumab either intravenous (IV) or subcutaneous (SC): 6 mg/kg IV every 3 weeks (3-weekly schedule), or 2 mg/kg IV weekly (weekly schedule)\*, or 600 mg SC every 3 weeks.

Chemotherapy (CT): vinorelbine, capecitabine or eribulin (according to investigator preference):

* Vinorelbine either oral (60 mg/m2) or IV (25 or 30 mg/m2 per investigator preference) on days 1 and 8, every 3 weeks.
* Capecitabine: 1250 or 1000 mg/m2 (per investigator preference) twice a day (BID) oral, 2 weeks on, 1 week off, every 3 weeks.
* Eribulin: 1.23 mg/m2 IV on days 1 and 8, every 3 weeks.

  * If using trastuzumab IV, a loading dose of 8 mg/kg (for the 3-weekly schedule), or 4 mg/kg (for the weekly schedule) is necessary if more than 6 weeks have passed since the previous trastuzumab dose.

6 mg/kg IV every 3 weeks (3-weekly schedule), or 4 mg/kg IV loading dose, followed by 2mg/kg IV weekly (weekly schedule)\*, or 600 mg SC every 3 weeks.

\* If using trastuzumab IV, a loading dose of 8 mg/kg (for the 3-weekly schedule), or 4 mg/kg (for the weekly schedule) is necessary if more than 6 weeks have passed since the previous trastuzumab dose.

500 mg intramuscular every 4 weeks plus loading dose on day 15 cycle 1.

Oral (60 mg/m2) or IV (25 or 30 mg/m2 per investigator preference) on days 1 and 8, every 3 weeks.

1250 or 1000 mg/m2 (per investigator preference) twice a day (BID) oral, 2 weeks on, 1 week off, every 3 weeks.

1.23 mg/m2 IV on days 1 and 8, every 3 weeks.

Eribulin

Study Director

Randomized phase III trial of trastuzumab + Alpelisib +/- fulvestrant versus trastuzumab + chemotherapy in patients with PIK3CA mutated previously treated HER2+ Advanced Breast cancer.

This is an international, multicenter, open-label, controlled phase III randomized clinical trial in HER2+ advanced breast cancer (ABC) patients harboring PIK3CA mutation.

Approximately 300 patients (144 in the Hormone Receptor (HR)- cohort and 156 in the HR+ cohort) will be enrolled.

Central screening of PIK3CA mutations on the most recent available formalin-fixed paraffinembedded (FFPE) tumor sample is required for the purpose of eligibility. Investigators will be encouraged to send the most recent tumor tissue, preferably from a metastatic lesion. However, if this is not possible, archived tissue samples either from primary tumor or metastatic lesion will be acceptable. Local screening of HR and HER2 status is required (although there will be a central confirmation done retrospectively).

Once the screening process (locally at each site and at the central laboratory) is completed, fully eligible patients will be randomized in a 1:1 fashion to the control arm with trastuzumab plus chemotherapy (CT) or to the experimental arm with trastuzumab + alpelisib +/- fulvestrant (depending on HR status). The two patient cohorts defined according to HR status will be randomized separately, with randomization in each cohort stratified by prior treatment with pertuzumab (yes vs no) and number of prior anti-HER2 based therapy lines for MBC (≤2 vs \>2).

In both cohorts patients will continue to receive their assigned treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurs first.

After objective disease progression, patients in both treatment arms will be followed until death or withdrawal of consent.

In order to perform exploratory biomarker analysis, pre-treatment tumor and sequential blood samples (at baseline, at week 9, at the end of treatment (EOT), and at progressive disease (PD)) will be obtained. Additionally, blood samples from approximately 100 patients (50 HR+ and 50 HR-) screened and without PIK3CA mutation will be collected.

Trastuzumab + Alpelisib +/- Fulvestrant vs Trastuzumab + CT in Patients With PIK3CA Mutated Previously Treated HER2+ Advanced BrEasT Cancer (ALPHABET)

A Randomized Phase III Trial of Trastuzumab + ALpelisib +/- Fulvestrant Versus Trastuzumab + Chemotherapy in Patients With PIK3CA Mutated Previously Treated HER2+ Advanced BrEasT Cancer. "ALPHABET Study".

Time from randomization to the initiation of the first subsequent line of systemic therapy after the study therapy or death from any cause.

Time from randomization to the cessation of the first subsequent line of systemic therapy for any reason (i.e., progression, toxicity, death from any cause, etc.).

NFBSI-16 is a 16-item assessment of disease-related symptoms, treatment side effects, and general function and well-being. The instrument has 3 subscales: disease-related symptoms (DRS) - 9 items; treatment side-effects (TSE) - 4 items; and general function and well-being (F/WB) - 3 items. All items have a 7-day recall period and a 5-point verbal descriptive response scale ranging from 0 ("not at all") to 4 ("very much"). NFBSI-16 summary scores range from 0-64, with higher scores indicating less symptomatology and better QoL. Scoring of summary and subscale scores will be based on the FACIT.org scoring guidelines.

Patients must complete each paper-based QoL questionnaire during their visits in the clinic and prior to having any tests and to any discussion of their health status with healthcare personnel at the site.

A longitudinal assessment will be used to assess differential effects of the randomized treatments on patients' QoL

Time from randomization to the first time the patient's NFBSI-16 summary score shows a ≥ 4 points decrease from baseline for at least two consecutive assessments, or an initial score decrease of ≥ 4 points followed by death before the next assessment timepoint.

Time from randomization to objective disease progression based on the investigator's assessment according to the response evaluation criteria for solid tumors (RECIST) version 1.1., or death from any cause.

Time from randomization to death from any cause.

Complete or partial response as best overall response based on the investigator's assessment according to RECIST version 1.1.

Adverse events (AEs) grades will be defined by the National Cancer Institute common terminology criteria for adverse events (NCI-CTCAE) version 5.0. AE terms will be coded according to the MedDRA dictionary.

ETOP IBCSG Partners Foundation

Breast International Group

Novartis Pharmaceuticals

Spanish Breast Cancer Research Group

Digestive System Diseases

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Pharmaceutical Solutions

Irinotecan

Cetuximab

Fluorouracil

Oxaliplatin

MEN1611 oral dose administered twice daily for a continuous 28-day cycle.

MEN1611

Cetuximab solution for infusion administered weekly via IV infusion.

Josep Tabernero, MD PhD

Open-label, dose-confirmation and cohort expansion, multicentre, Phase Ib/II study to assess the anti-tumour activity and safety of MEN1611 in combination with cetuximab for the treatment of patients with PIK3CA mutated metastatic colorectal cancer.

This Phase Ib/II study will investigate the anti-tumour activity and safety of daily oral doses MEN1611 in combination with cetuximab in female and male patients affected by PIK3CA mutated, N-K-RAS wild-type and BRAF wild-type metastatic colorectal cancer.

MEN1611 is a potent, selective Class I phosphoinositide 3-kinase (PI3K) inhibitor. The Maximum Tolerated Dose (MTD) of MEN1611 given as single agent was assessed in a phase I trial in patients with advanced solid tumors.

This Phase Ib/II will start with a dose confirmation part (Step 1) to identify the RP2D of MEN1611 given in combination with cetuximab.

The study will continue with a cohort expansion (Step 2) to explore the anti-tumour activity of the selected MEN1611 dose level combined with cetuximab with further assessment of their safety and tolerability.

Step 1: Confirmation of Dose for Cohort Expansion / Step 2: Cohort Expansion

MEN1611 With Cetuximab in Metastatic Colorectal Cancer (C-PRECISE-01)

Open-label, Multicentre, Phase Ib/II Study of MEN1611, a PI3K Inhibitor, and Cetuximab in Patients With PIK3CA Mutated Metastatic Colorectal Cancer Failing Irinotecan, Oxaliplatin, 5-FU and Anti-EGFR Containing Regimens

Determination of the recommended phase II dose of MEN1611 when administered orally in combination with cetuximab to patients with PIK3CA mutated colorectal cancer failing irinotecan, oxaliplatin, 5-FU and anti-EGFR containing regimens.

Assessment of the anti-tumour activity of MEN1611 in combination with cetuximab in patients with PIK3CA mutated metastatic colorectal cancer failing irinotecan, oxaliplatin, 5-FU and anti-EGFR containing regimens.

Assessment of the tolerability of MEN1611 in combination with cetuximab according to NCI CTCAE v5.0.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Detection of Tumor DNA in the Blood of Patients Receiving Standard Therapy for Hormone Receptor-positive (HR+) Non-HER2 Expressing (HER2-) Metastatic Breast Cancer as a Tool to Select Those Who May Benefit From the Next Course of Fulvestrant in Combination With Alpelisib or Ribociclib	NCT05625087	Breast Cancer S...	Alpelisib Ribociclib	18 Years -	UNICANCER
Trastuzumab + Alpelisib +/- Fulvestrant vs Trastuzumab + CT in Patients With PIK3CA Mutated Previously Treated HER2+ Advanced BrEasT Cancer (ALPHABET)	NCT05063786	Advanced Breast...	Trastuzumab Alpelisib Fulvestrant Vinorelbine Capecitabine Eribulin	18 Years -	Spanish Breast Cancer Research Group
Trastuzumab + Alpelisib +/- Fulvestrant vs Trastuzumab + CT in Patients With PIK3CA Mutated Previously Treated HER2+ Advanced BrEasT Cancer (ALPHABET)	NCT05063786	Advanced Breast...	Trastuzumab Alpelisib Fulvestrant Vinorelbine Capecitabine Eribulin	18 Years -	Spanish Breast Cancer Research Group
MEN1611 With Cetuximab in Metastatic Colorectal Cancer (C-PRECISE-01)	NCT04495621	Metastatic Colo...	MEN1611 Cetuximab	18 Years -	Menarini Group

Spots Global Cancer Trial Database for pik3ca mutated