| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic hormone receptor positive breast cancer (primary or recurrent), defined as ER+ >1% in metastatic biopsy (archival material or study biopsy) and HER2 negative in the last biopsy evaluable for HER2. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hormone receptor positive breast cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Assessment of toxicity of combined treatment with ipilimumab, nivolumab, pegylated liposomal doxorubicin and cyclophosphamide (ipi/nivo/chemo)
Assessment of clinical response in ipi/nivo/chemo group compared to chemo only group: Progression-free survival (PFS); compare the PFS rates when 95% of patients in the control croup have PD |
|
| E.2.2 | Secondary objectives of the trial |
Assessment of clinical response in ipi/nivo/chemo group compared to chemo only group: Objective tumor response rate (ORR), duration of response (DR), durable tumor response rate (DRR; >6 months), clinical benefit rate (CBR), overall survival (OS)
Assessment of toxicity of ipi/nivo (without chemotherapy) in cross-over arm
Assessment of ORR, DR, DRR, PFS and OS in cross-over arm receiving ipi/nivo (without chemotherapy)
Assessment of PD-L1 expression, mutation load and immune gene expression as biomarkers for clinical response
Assessment of patient reported outcomes, as measured by the Chalder Fatigue Questionnaire (FQ), an 11 point Numerical Rating Scale (NRS) for pain intensity and EORTC QLQ-C15-PAL
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Metastatic hormone receptor positive breast cancer (primary or recurrent), defined as ER+ >1% in metastatic biopsy (archival material or study biopsy) or cytology and HER2 negative in the last biopsy or cytology evaluable for HER2. HER2-analysis is to be perfomed according to national criteria.
2. Adequate core or excisional study biopsy of a tumor lesion. Lesions in previously irradiated areas may only be used for the biopsy if the lesion has appeared or progressed after radiation. . No anti-tumor treatment is allowed between the time point for biopsy and study entry.
3. Measurable metastatic disease according to RECIST
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Signed Informed Consent Form
6. Women or men aged ≥ 18 years
7. A minimum of 12 months from adjuvant/neoadjuvant chemotherapy with antracyclins to relapse of disease.
8. A maximum of one previous line with chemotherapy in the metastatic setting
9. Chemotherapy is considered as preferred treatment
10. Previous endocrine and targeted therapy is allowed
11. No use of systemic corticosteroids at study entry
12. Female subject of childbearing potential should have a negative urine or serum pregnancy within 7 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
13. Female subjects of childbearing potential should agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year, during the treatment period and for at least 5 months after the last dose of study therapy.
14. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 7 months after the last dose of study therapy
15. Able to swallow and retain orally administered medication
16. Adequate organ function as defined in Table 1 |
|
| E.4 | Principal exclusion criteria |
1. Malignancies other than breast cancer within 5 years prior to randomization
2. Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 2 weeks prior to randomization
3. Known CNS disease, except for asymptomatic CNS metastases, provided all of the following criteria in the protocol are met.
4. Uncontrolled pleural effusion, pericardial effusion, or ascites. Patients with indwelling catheters are allowed
5. Uncontrolled tumor-related pain. Patients requiring narcotic pain medication must be on a stable regimen at study entry. Symptomatic lesions amenable to palliative radiotherapy should be treated prior to randomization. Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain should be considered for loco-regional therapy if appropriate prior to randomization
6. Ionized calcium > 1.2 x UNL.
7. Pregnant or breastfeeding
8. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease
9. Significant cardiovascular disease. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF < 50% must be on a stable medical regimen that is optimized
10. Severe infection within 21 days prior to randomization, requiring hospitalization
11. Received oral or IV antibiotics within 1 week prior to Cycle 1, Day 1.
12. Major surgical procedure within 21 days prior to randomization or anticipation of the
need for a major surgical procedure during the course of the study other than for diagnosis.
13. A history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
14. Known hypersensitivity to any of the components of the investigational products
15. A history of autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment.
Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only are permitted provided that they meet all of the following conditions defined in the protocol.
16. Undergone allogeneic stem cell or solid organ transplantation
17. A history of idiopathic pulmonary fibrosis or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
18. A positive test for HIV
19. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C.
20. Active tuberculosis
21. Currently receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
22. Received treatment with immune checkpoint modulators
23. Received treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of the drug (whichever is shorter) prior to randomization
24. Received treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to randomization, or anticipated requirement for systemic immunosuppressive medications during the trial
a. Patients who have received acute, low-dose, systemic immunosuppressant medications may be enrolled in the study
b. Patients with a history of allergic reaction to IV contrast requiring steroid pre-treatment should have baseline and subsequent tumor assessments performed using MRI
c. The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed
25. Received anti-cancer therapy (medical agents or radiation) within 2 weeks prior to study Cycle 1, Day 1. Palliative radiotherapy for bone lesions is allowed up to 7 days before start of therapy.
26. A history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial
27. Known psychiatric or substance abuse disorders that would interfere with cooperation and the requirements of the trial
28. Received a live vaccine within 30 days of planned start of study therapy, or is expected to receive such a vaccine while on therapy
a. Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines
29. Any reason why, in the opinion of the investigator, the patient should not participate
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Assessment of toxicity
Progression-free survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Compare the PFS rates when 95% of patients in the control croup have PD |
|
| E.5.2 | Secondary end point(s) |
| Objective tumor response rate (ORR), duration of response (DR), durable tumor response rate (DRR; >6 months), overall survival (OS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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
|
| Follow-Up Phase: The patients that progressed during study treatment will be assessed at one Follow-up visit 16 weeks after discontinuation. Patients who discontinue without progression will be assessed every 12 weeks for the next 12 months. Every effort should be made to collect information regarding disease status until the start of new anti-neoplastic therapy, disease progression, death, or end of the study. Survival data will be collected for 5 years after inclusion of the last patient. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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