| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Solid tumors
Hormone receptor positive breast cancer
Ovarian cancer |
Tumores sólidos
Cancer de mama con receptor hormonal positivo
Cancer de ovario |
|
| E.1.1.1 | Medical condition in easily understood language |
Solid tumors
Breast cancer
Ovarian cancer |
Tumores sólidos
Cancer de mama
Cancer de ovario |
|
| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Phase IB
To estimate the maximum tolerated dose MTD(s) and/or identify the recommended phase II dose(s) of BYL719 in combination with AMG 479 (ganitumab) in selected patients with solid tumors
Phase II
To estimate the antitumor activity of BYL719 in combination with AMG 479 (ganitumab) in the following Phase II populations:
Arm 1: Patients with PIK3CA mutated or amplified hormone receptor positive breast cancer
Arm 2: Patients with PIK3CA mutated or amplified ovarian cancer |
Fase IB
Estimar la máxima dosis tolerada (MTDs) y / o identificar la dosis recomendada para la fase II de BYL719 en combinación con AMG 479 (ganitumab) en pacientes con tumores sólidos.
Fase II
Estimar la actividad antitumoral de BYL719 en combinación con AMG479 (ganitumab) en la siguiente población de pacientes:
Brazo 1: Pacientes con cancer de mama con PIK3CA mutado o amplificado o receptor hormonal positivo.
Brazo 2: Pacientes con cáncer de ovario con PIK3CA mutado o amplificado |
|
| E.2.2 | Secondary objectives of the trial |
Phase Ib and II:
? To characterize the safety and tolerability of BYL719 and AMG 479 (ganitumab) in combination
? To determine the single dose (AMG 479 and BYL719) and multiple dose (BYL719) PK profile of the investigational drugs in combination |
Fase Ib y II:
-Caracterizar la seguridad y tolerabilidad de BYL719 y AMG479 (ganitumab) en combinación
-Determinar el perfil PK de dosis única (AMG479 y BYL719) y dosis múltiple de los fármacos en combinación. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent must be obtained prior to any screening procedures.
2. Patients aged ? 18 years (male or female).
3. Patients with the following histologically/cytologically-confirmed advanced solid tumors with documented somatic PIK3CA mutations or amplifications in tumor tissue (based on available local documentation i.e. pathology report at the site), for whom according to the
assessment of the investigator no standard therapy exists: For dose escalation (phase Ib) only:Hormone receptor positive breast carcinoma, Ovarian carcinoma, Other tumors upon agreement with Novartis
For phase II Arm 1 only: Patients with PIK3CA mutated or amplified hormone receptor positive breast carcinoma
For phase II Arm 2 only: Patients with PIK3CA mutated or amplified ovarian carcinoma
4. Fresh tumor biopsy must be collected at baseline from all patients enrolled to enable the analyses described in the protocol.
5. Patients must have relapsed or progressed following standard therapy or patients for whom no standard anticancer therapy according to investigator assessment exists.
6. Measurable disease as determined by RECIST v1.1. Target lesions in previously irradiated areas should not be selected unless there is clear evidence of progression in such lesions.
7. World Health Organization (WHO)/ Eastern Cooperative Oncology Group (ECOG)) Performance Status (PS) ? 2.
8. Adequate organ function and laboratory parameters as defined by: (ANC) ? 1.5 x 109/L, Hemoglobin (Hgb) ? 9g/dl, Platelets (PLT) ? 100 x 109/L without transfusions within 60 days before first treatment, AST/SGOT and/or ALT/SGPT ? 2.5 x ULN or ? 5 x ULN if liver metastases are present, Serum bilirubin ? 1.5 x ULN, Serum creatinine ? 1.5 x ULN or calculated or directly measured CrCl ? 50% LLN
9. Recovery from all AEs of previous anti-cancer therapies, including surgery and radiotherapy, to baseline or to CTCAE Grade ? 1, except for alopecia.
10. Negative serum pregnancy (?-hCG) test within 72 hrs before starting study treatment in all pre-menopausal women and women < 12 months after the onset of menopause |
1. Consentimiento informado por escrito
2. Pacientes ? 18 años (hombres o mujeres)
3. Pacientes con tumores sólidos avanzados con confirmación histológica/citológica documentada y mutación o amplificación de PIK3CA. Para la fase de escalado (Ib): Cáncer de mama con receptor hormonal positivo, cáncer de ovario, u otros tumores bajo autorización del sponsor. Para la fase II -Brazo 1: pacientes con cáncer de mama con PI3CA mutado o receptor hormonal positivo. Para la fase II- Brazo 2: pacientes con cáncer de ovario con PIK3CA mutado o amplificado
4. Biopsia de tumor fresca debe ser recogida en el screening para todos los pacientes.
5. Pacientes que han progresado después de terapia estándar para los que no exista otra terapia eficaz según el investigador
6. Enfermedad medible determinada por criterios RECIST v1.1.
7. WHO / ECOG (PS) ? 2.
8. Deben tener los siguientes valores de laboratorio: ANC? 1.5 x 109/L, Hemoglobina (Hgb)? 9g/dl, Plaquetas ? 100 x 109/L (sin transfusiones los últimos 60 dias), AST/SGOT y/o ALT/SGPT ? 2.5 x ULN o ? 5 x ULN si existen metastasis hepáticas, bilirubina sérica ? 1.5 x ULN, creatinina ? 1.5 x ULN CrCl ? 50% LLN
9. Recuperado de todos los AEs relacionados con terapias anti-cancerígenas previas, incluyendo cirugía y radioterapia a nivel basal o grado ? 1, excepto alopecia.
10. Test de embarazo negativo (?-hCG) comprobado en test de embarazo en las 72h horas antes de empezar el tratamiento en todas las mujeres pre-menopáusicas o mujeres < 12 meses después del inicio de la menopausia. |
|
| E.4 | Principal exclusion criteria |
1. Prior therapy with PI3Ki- or IGF-1R
2. Patients with known history of severe infusion reactions to monoclonal antibodies.
3. Patients with primary CNS tumor or CNS tumor involvement. However, patients with
metastatic CNS tumors may participate in this study if the patient is: 4 weeks from prior therapy completion (including radiation and/or surgery) and, Clinically stable with respect to the CNS tumor at the time of study entry and, Not receiving steroid therapy and, Not receiving anti-convulsive medications (that were started for brain metastases)
4. Patients who have received prior systemic anti-cancer treatment within the following time frames: Cyclical chemotherapy within a period of time that is shorter than the cycle length used for that treatment (e.g. 6 weeks for nitrosourea, mitomycin-C) prior to starting study treatment, Biologic therapy (e.g. antibodies), continuous or intermittent small molecule therapeutics, or any other investigational agents within a period of time which is ? 5 t1/2 or ? 4 weeks (whichever is shorter) prior to starting study treatment
5. Patients who have received radiotherapy ? 4 weeks prior to starting study drug, with exception of palliative radiotherapy, who have not recovered from side effects of such therapy and/or from whom ? 30% of the bone marrow was irradiated.
6. Patients who have undergone major surgery ? 4 weeks prior to starting study treatment or who have not recovered from side effects of such procedure.
7. History of thromboembolic event requiring full-dose anti-coagulation therapy any time prior to enrollment.
8. Clinically significant cardiac disease or impaired cardiac function, such as: Clinically significant heart disease such as CHF requiring treatment (NYHA Grade ? 2), LVEF < 50% as determined by MUGA scan or echocardiogram (ECHO), or uncontrolled arterial hypertension defined by blood pressure > 140 (systolic) /100 (diastolic) mmHg at rest (average of 3 consecutive readings), History or current evidence of clinically significant cardiac arrhythmias, atrial fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome, high-Grade/complete AV-blockage, History/evidence of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass graft (CABG), coronary angioplasty, or stenting), < 6 months prior to screening, QTcF > 480 msec on screening ECG, Complete left bundle branch block, Right bundle branch block + left anterior hemiblock (bifascicular block)
9. Patients with diabetes mellitus requiring insulin treatment or with fasting plasma glucose ? 125 mg/dL (6.9 mmol/L) and/or HbA1c > 5.9%.
10. Patients with peripheral neuropathy CTCAE Grade ? 2.
11. Patients with diarrhea CTCAE Grade ? 2.
12. Patients with acute or chronic pancreatitis.
13. Any other condition that would, in the Investigator?s judgment, contraindicate patient?s participation in the clinical study due to safety concerns or compliance with clinical study procedures,
14. Impaired GI function or GI disease that may significantly alter the absorption of oral
BYL719
15. Patients who are currently receiving medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug treatment.
16. Patients treated with hematopoietic colony-stimulating growth factors (e.g. G-CSF, GMCSF, M-CSF) ? 2 weeks prior to starting study drug. Erythropoietin or darbepoetin is allowed as long as it has been initiated at least 2 week prior to study enrollment.
17. Patients who have received systemic corticosteroids ? 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment.
18. History of another malignancy within 2 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix.
19. Known positive serology for HIV, active Hepatitis B, and/or active Hepatitis C infection.
20. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive Hcg laboratory test (> 5 mIU/mL).
21. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, are not allowed to participate in this study UNLESS they are using
highly effective methods of contraception throughout the study and for 3 months after
study drug discontinuation.
22. Sexually active males must use a condom during intercourse while taking the drugs and for 6 months after stopping treatment and should not father a child in this period. A
condom is required to be used also by vasectomized men in order to prevent delivery of the drugs via seminal fluid. |
1. Terapia previa con PI3Ki- o IGF-1R.
2. Pacientes con historia conocida de reacciones severas a la infusión de anticuerpos monoclonales.
3. Pacientes con tumores primarios en el SNC o afectación del SNC. Sin embargo, pacientes con tumores metastásicos en el SNC pueden participar si el paciente ha completado el tratamiento hace más 4 semanas (incluyendo radiación y/o cirugía) y son clínicamente estables en el momento de entrar en el estudio.
4. Pacientes que esten recibiendo terapias sistemicas para el cáncer: quimioterapia durante un periodo inferior al ciclo habitual de ese tratamiento antes de empezar el tratamiento del estudio, terapia biológica, terapia continua o intermitente de terapia de molecular pequeña u otros agentes en investigación durante un periodo que sea ? 5 t1/2 o ? 4 semanas (el que que sea menor) antes de iniciar el tratamiento del estudio
5. Pacientes que hayan recibido radioterapia ? 4 semanas antes de iniciar el tratamiento del estudio, a excepción de radioterapia paliativa, los pacientes deben haberse recuperado de sus efectos de esta terapia o que ? 30% de medula osea fuera irradiada.
6. Pacientes sometidos a cirugía ? 4 weeks antes de iniciar el tratamiento del ensayo o que no se hayan recuperado de sus efectos.
7. Historial de eventos de trombiembolismo y que requieren dosis plenas de terapia anti-coagulante en cualquier momento antes de la randomización.
8. Enfermedad cardíaca clínicamente significativa o función cardíaca alterada: enfermedad cardíaca clínicamente significativa que requiera tratamiento CHF (NYHA grado? 2), LVEF < 50% determinado por MUGA o ecocardiograma (ECHO), o hipertensión arterial no controlada definida por > 140 (sistolica) /100 (diastolica) mmHg en reposo (media de 3 lecturas consecutivas), historial o evidencia actual de arritmias cardíacas clínicamente significativas, fibrilación atrial y/o anormalidades en la conducción, ej. síndrome de QT prolongado, bloqueo AV de alto grado/completo, Historia / evidencia de síndromes coronarios agudos (incluyendo infarto de miocardio, angina inestable, revascularización coronaria (CABG), angioplastia coronaria o colocación de stent), <6 meses anteriores a la selección , QTcF> 480 ms en el ECG, bloqueo completo de rama izquierda, bloqueo de rama derecha + hemibloqueo anterior izquierdo (bloqueo bifascicular)
9. Pacientes con diabetes mellitus que requieran tratamiento con insulina o con glucos en ayunas ?125 mg/dL (6.9 mmol/L) and/or HbA1c > 5.9%.
10. Pacientes con neuropatía periférica CTCAE Grado ? 2.
11. Pacientes con diarrea CTCAE Grado ? 2.
12. Pacientes con pancreatitis aguda o crónica.
13. Cualquier otra condición, que a criterio médico contraindique la participación del paciente en el estudio debido a criterios de seguridad o cumplimiento con los procedimientos del estudio.
14. Afectación de la función GI o enfermedad GI que puede afectar significativamente la absorción oral de BYL719
15. Pacientes que estén recibiendo tratamiento con alguna medicación que tiene riesgo de prolongación del intervalo QTcF o de inducir Torsades de Pointes y no puede ser retirada o cambiada a un fármaco alternativo antes del inicio del tratamiento.
16. Pacientes que estan siendo tratados con factores de crecimiento hematopoiéticos
(ej. G-CSF, GMCSF, M-CSF) ? 2 semanas antes de empezar el tratamiento del estudio. Eritropoietina o darbepoetina se permiten si se han iniciado al menos 2 semanas antes del inicio del tratamiento del estudio.
17. Pacientes que han recibido corticosteroides sistémicos ? 2 2 semanas antes del inicio del tratamiento del estudio o que no se hayan recuperado completamente de los efectos de su tratamiento.
18. Historial de cualquier malignidad durante los últimos 2 años exepcto carcinoma de células basales de piel o carcinoma in situ de cuello uterino.
19. HIV conocido, hepatitis B, y/o infección activa por hepatitis C
20. Mujeres embarazadas o lactantes.
21. Mujeres en edad fertil, definidas como toda mujer fisiológicamente capaz de quedarse embarazada, a menos que estén utilizando métodos anticonceptivos eficaces durante la dosificación del tratamiento del estudio.
22. Hombres sexualmente activos a menos que utilicen un preservativo durante las relaciones sexuales mientras toman el fármaco y durante 28 dias después de finalizar la medicación del estudio y no deben engendrar un hijo en este periodo. Es necesario utilizar un preservativo también para los hombres vasectomizados para evitar la liberación del fármaco a través del líquido seminal. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase IB
Incidence of dose limiting toxicities (DLTs) in Cycle 1
Phase II
Objective response rate (ORR) as per RECIST 1.1 |
Fase IB
Incidencia de toxicidades limitantes de dosis (DLTs) en el ciclo 1
Fase II
Tasa de respuesta objetiva (ORR) según RECIST 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase IB
Cycle 1: 28 days
Phase II
Approximately 6 months |
Fase IB
Ciclo 1: 28 dias
Fase II
Aproximadamente 6 meses |
|
| E.5.2 | Secondary end point(s) |
Phase Ib and II:
? Adverse events, serious adverse events, changes in hematology or chemistry values, vital signs, ECGs
? Basic PK parameters |
Fase Ib y II
-Acontecimientos adversos, acontecimientos adversos graves, cambios en los valores de hematologia o bioquímica, signos vitales, ECGs
-Parámetros farmacocinéticos |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase IB - Approximately 6 months;
Phase II : Ciclo 1 |
Fase IB: aproximadamente 6 meses
Fase II: Ciclo 1 |
|
| 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 | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose escalation study of BYL719 and AMG 479 in selected patients with solid tumors |
| Estudio de escalado de dosis de BYL719 y AMG479 en pacientes con tumores sólidos selecionados |
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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 | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| Phase Ib and II of the study will end when the treatment period, safety follow-up, disease follow-up and survival follow-up (only for phase II) have ended for all patients as described in Section 7.1.4 of the protocol, or when the study is terminated early. |
| Fase Ib y II del estudio finalizarán cuando el periodo de tratamiento, seguimientos de seguridad, seguimiento de la enfermedad y seguimiento de superviciencia (solo en fase II) finalicen para todos los pacienets como se describe en la sección 7.1.4 del protocolo, o cuando el ensayo se finalice prematuramente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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