| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| PIK3CA mutated, HR+/Her2- metastatic breast cancer who do not present progressive disease after 6-8 cycles of 1st or second line chemotherapy. |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To determine whether treatment with alpelisib plus fulvestrant prolongs progression-free survival (PFS) compared to maintenance chemotherapy in patients PIK3CA mutated with hormone receptor positive (HR+), HER2-negative advanced breast cancer, who do not present a progressive disease after 6-8 cycles of chemotherapy.
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| E.2.2 | Secondary objectives of the trial |
- To pool data from a sample of patients from the SAFIR-PI3K trial with the SAFIR02 Breast trial data in order to address the primary objective of the SAFIR02 Breast trial.
- To compare overall survival
- To evaluate overall response rates and change in tumor size in each arm
- To evaluate the safety of each arm
- To compare overall survival in the pooled data from the SAFIR02 Breast trial and the sample of patients of the SAFIR-PI3K trial
- To evaluate overall response rates and change in tumor size in each arm in the pooled data from the SAFIR02 Breast trial and the sample of patients of the SAFIR-PI3K trial
- To evaluate the safety of each arm in the pooled data from the SAFIR02 Breast trial and a sample of patients from the SAFIR-PI3K trial
- To merge part of the SAFIR-PI3K study data to the SAFIR02 Breast trial in order to perform a prospective pooled analysis of SAFIR02 Lung and SAFIR02 Breast studies
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- To correlate molecular characteristics of the patients with the efficacy endpoints (response rate, progression-free and overall survival).
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1/ To correlate pAKT with benefit, and presence of subclonal PTEN alteration in ctDNA at baseline with resistance
2/ To complete the additional research objectives of the SAFIR02 protocol, which are :
i/Circulating tumor DNA analysis to investigate: a/ correlation of ctDNA profiles with those obtained with NGS in the tumor sample; b/ identification of molecular alterations linked to resistance to targeted therapies (meets item 1).
ii/ Validation of the functional protein activation and exploration of the sequence of events in the signalling pathways, using FISH and CISH, IHC staining, kinome arrays and RPPA analysis.
iii/ Investigation of molecular changes that underlie disease progression and the formation of metastases a/ using whole exome sequencing program on normal cells, primary and metastatic tumor material; b / comparing the variation on molecular profiles from different metastatic sites.
iv/ Construction of a virtual cell to develop the optimal algorithm able to identify the driver alterations and then to deliver the optimal choice of therapy.
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| E.3 | Principal inclusion criteria |
1. Women (or men) with histologically confirmed metastatic breast cancer.
2. Hormone receptor positive (HR+) and no Her2 over-expression, according to local assessment.
3. Presence of PIK3CA mutation on exon 9 or 20, determined on metastatic tissue specimen (frozen or FFPE) or plasma (ctDNA). Eligible plasma should have been collected at time of metastatic disease progression and before to initiating chemotherapy.
4. Patient’s disease is resistant to endocrine therapy (defined either as a relapse or progression occurred during endocrine therapy, whatever the line, or less than 12 months after the end of endocrine therapy in adjuvant context).
5. Patients who received 6 to 8 cycles of a first line chemotherapy, or patients who received 6 to 8 cycles of a first line stopped for progression followed by 6 to 8 cycles of a 2nd line chemotherapy, and who are presenting a stable or a responding disease at the time of randomization (4 full cycles of chemotherapy are accepted if stopped for toxicity reasons).
6. Age ≥ 18 years
7. WHO Performance Status 0/1
8. Presence of measurable or evaluable disease according to RECIST criteria v1.1
9. Patients will have had a wash-out period of at least 14 days for weekly (except monoclonal antibodies) or daily chemotherapies or 28 days for other chemotherapies from last chemotherapy administration prior to randomization and should have recovered from all residual toxicities (grade ≤1), excluding alopecia.
10. Patient has adequate bone marrow and organ function as defined by the following laboratory values:
a. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
b. Platelets ≥ 100 x 109/L
c. Hemoglobin ≥ 9.0 g/dL
d. INR ≤ 1.5
e. Potassium, magnesium and calcium (corrected for albumin), within normal limits for the institution, or ≤ Grade 1 severity according to NCI-CTCAE version 4.03 if judged clinically not significant by the investigator
f. Serum creatinine ≤ 1.5 x ULN and/or creatinine clearance ≤ 50mL/min (Measured or calculated by Cockroft and Gault formula)
g. Total serum bilirubin ≤ ULN (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert’s Syndrome)
h. Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤ 2.5 ULN (or < 5.0 x ULN if liver metastases are present)
i. Fasting plasma glucose (FPG) ≤ 140mg/dL or ≤ 7.7 mmol/L* and Glycosylated Hemoglobin (HbA1c)≤ 6.4% (both criteria have to be met).
* For patients with FPG ≥ 100 mg/dL and/or HbA1c ≥5.7% (i.e. threshold for pre-diabetes) at baseline, recommend lifestyle changes according to ADA guidelines, i.e. dietary advice (e.g. small frequent meals, low carbohydrate content, high fiber, balancing carbohydrate intake over the course of the day, three small meals and 2 small snacks rather than one large meal) and exercise. A consultation with a diabetologist is highly recommended
11. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analysis
12. Patient with social insurance coverage. |
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| E.4 | Principal exclusion criteria |
1. Spinal cord compression and/or symptomatic or progressive brain metastases (unless asymptomatic or treated and stable without steroids during the last 30 days).
2. Patient has received more than 2 previous lines of chemotherapy for metastatic disease before randomization.
3. In the Investigator’s judgment, patient has a life expectancy < 3 months .
4. Disease progression occuring before randomization.
5. Patient has received prior treatment with any PI3K or AKT inhibitor (mTOR inhibitors are allowed)
6. Patient has history of hypersensitivity to any drugs or metabolites of similar chemical classes as alpelisib, or history of hypersensitivity to active or inactive excipients of any other study treatment
7. Patient has not recovered to grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy
8. Patient has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to randomization, and who has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia) and/or from whom ≥ 25% of the bone marrow was irradiated
9. Patient has participated to another clinical study with an investigational product during the last 30 days.
10. Patient has had major surgery within 14 days prior to starting study treatment or has not recovered from major side effects
11. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study treatment, or has not fully recovered from side effects of such treatment (grade ≤1).
12. Patients with an established diagnosis of diabetes mellitus type I or not controlled type II, or documented steroid induced diabetes mellitus
13. Patient who necessitates to maintain the following drugs during study treatment:
• Drugs known to be strong inhibitors or inducers of isoenzyme CYP3A4 including herbal medications (list of prohibited CYP3A4 inhibitors and inducers provided in Table 12)
• Drugs with a known risk to induce Torsades de Pointes (list of prohibited QT prolonging drugs provided in Table 12)
Note: The patient must have discontinued strong inducers for at least one week and must have discontinued strong inhibitors before the study treatment is initiated. Switching to a different medication prior to starting study treatment is allowed.
14. Patient is currently receiving warfarin or other coumarin derived anti-coagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed.
15. Patients who have other concurrent severe and/or uncontrolled medical conditions that would, in the Investigator’s judgment, contraindicate patient participation in the individual patient program (eg. active or uncontrolled severe infection, chronic active hepatitis, immuno-compromised, acute or chronic pancreatitis, uncontrolled high blood pressure, interstitial lung disease, etc.)
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16. Patient has currently documented pneumonitis
17. Patient has a known history of HIV infection (testing not mandatory)
18. Patient has any of the following cardiac abnormalities:
• symptomatic congestive heart failure
• history of documented congestive heart failure (New York Heart Association functional classification III-IV), documented cardiomyopathy
• Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)
• myocardial infarction ≤ 6 months prior to enrolment
• unstable angina pectoris
• serious uncontrolled cardiac arrhythmia
• symptomatic pericarditis
• QTcF > 480 msec on the baseline ECG (using the QTcF formula) currently receiving treatment with medication that has a known risk to prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to starting study treatment (list of prohibited QT prolonging drugs provided in Table 12)
19. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of any study treatment (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
20. Patient had previous or current malignancies of other histologies within the last 5 years, with the exception of in situ carcinoma of the cervix, and adequately treated basal cell or squamous cell carcinoma of the skin.
21. Pregnant or nursing (lactating) women.
22. Patient who does not accept to comply with highly effective contraception methods during the study treatment and through the duration as defined below after the final dose of study treatment:
• Sexually active males should use a condom during intercourse while taking drug and for at least 4 weeks after the final dose of study treatment and should not father a child in this period.
• Women of child-bearing potential must use highly effective contraception during study treatment and through at least 4 weeks after the final dose of study treatment
23. Patient has a history of non-compliance to medical regimen or inability to grant consent
24. Individuals deprived of liberty or placed under the authority of a tutor
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| When the required number of events has been reached. |
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| E.5.2 | Secondary end point(s) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Construction of a virtual cell to develop the optimal algorithm able to identify the driver alterations and then to deliver the optimal choice of therapy. |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 30 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
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