| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Solid Tumors |
| Tumores sólidos avanzados |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced Solid Tumors |
| Tumores sólidos avanzados |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041067 |
| E.1.2 | Term | Small cell lung 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073071 |
| E.1.2 | Term | Hepatocellular carcinoma |
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060121 |
| E.1.2 | Term | Squamous cell carcinoma of head and neck |
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041823 |
| E.1.2 | Term | Squamous cell carcinoma |
| 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 |
- To characterize the safety and tolerability and to identify the recommended Phase 2 dose (RP2D) of ALKS 4230 administered subcutaneously (SC) as lead-in monotherapy and in combination with pembrolizumab in subjects with advanced solid tumors (Phase 1)
- To characterize the safety profile of SC ALKS 4230 at the RP2D in combination with pembrolizumab in subjects with advanced solid tumors (Phase 2)
- To estimate the clinical activity of combination treatment with ALKS 4230 and pembrolizumab in terms of objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1 separately for non–small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), squamous tumor agnostic, hepatocellular carcinoma (HCC), and small-cell lung cancer (SCLC) (Phase 2) |
• caracterizar la seguridad y tolerabilidad e identificar la dosis de fase 2 recomendada (DF2R) de ALKS 4230 administrado por vía subcutánea (SC) como monoterapia inicial y en combinación con pembrolizumab en sujetos con tumores sólidos avanzados (fase 1);
• caracterizar el perfil de seguridad de ALKS 4230 SC en la DF2R en combinación con pembrolizumab en sujetos con tumores sólidos avanzados (fase 2);
• estimar la actividad clínica de la politerapia con ALKS 4230 y pembrolizumab en términos de tasa de respuesta objetiva (TRO) según lo evaluado en Response Evaluation Criteria in Solid Tumors (RECIST) (Directrices de evaluación de respuesta en tumores sólidos) versión 1.1 por separado para cáncer de pulmón de células no pequeñas (CPCNP), carcinoma de células escamosas de cabeza y cuello (CCECC), tumor de células escamosas agnóstico, carcinoma hepatocelular (CHC) y cáncer de pulmón de células pequeñas (CPCP) (fase 2) |
|
| E.2.2 | Secondary objectives of the trial |
- To describe dose-limiting toxicity (DLT) for SC ALKS 4230 lead-in monotherapy (Phase 1)
- To characterize the pharmacokinetics (PK), clinical pharmacodynamics (PD), and immunogenicity of SC ALKS 4230 as lead-in monotherapy (Phase 1) and in combination with pembrolizumab (Phase 1 and Phase 2)
- To describe antitumor activity observed with SC ALKS 4230 as lead-in monotherapy and in combination with pembrolizumab (Phase 1)
- To evaluate antitumor efficacy in subjects treated with SC ALKS 4230 in combination with pembrolizumab (Phase 2) |
• describir la toxicidad limitante de la dosis (TLD) de la monoterapia inicial de ALKS 4230 SC (fase 1);
• caracterizar la farmacocinética (FC), la farmacodinámica (FD) clínica y la inmunogenia de ALKS 4230 SC como monoterapia inicial (fase 1) y en combinación con pembrolizumab (fase 1 y fase 2);
• describir la actividad antineoplásica observada con ALKS 4230 SC como monoterapia inicial y en combinación con pembrolizumab (fase 1);
• evaluar la eficacia antineoplásica en sujetos tratados con ALKS 4230 SC en combinación con pembrolizumab (fase 2) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is aged ≥18 years.
2. Subject or the subject’s legal representative provides written informed consent.
3. For Phase 1, Subject must have an advanced solid tumor (including lymphoma) and progressive disease following at least 1 line of therapy.
4. For Phase 2, subject must have one of the following tumor types or specific histology:
• NSCLC cohort: Subjects with Stage IIIB or IV NSCLC who have been treated with checkpoint inhibitors with stable disease or better and followed by progression more than 120 days after initiation of the checkpoint inhibitor therapy.
• SCCHN cohort: Subjects with recurrent or metastatic SCCHN with disease progression on or after chemotherapy and who have not received prior checkpoint inhibitor therapy.
• Squamous tumor agnostic cohort: Subjects with recurrent or metastatic squamous cell carcinoma following chemotherapy and who have not received prior checkpoint inhibitor therapy. Patients with SCCHN should enroll in the SCCHN cohort if they meet those eligibility criteria.
•HCC cohort: Subjects with recurrent or metastatic HCC with disease progression on or after antitumor therapy who have not received prior checkpoint inhibitor therapy.
• SCLC cohort: Subjects with unresectable or metastatic SCLC who have progressed on or after a minimum of 4 cycles of chemotherapy which may have included maintenance checkpoint inhibitor therapy. Subjects who have received prior checkpoint inhibitor therapy and had stable disease or better and who subsequently progressed are eligible provided that the progression was more than 120 days of the initiation of checkpoint inhibitor therapy.
5. Subject must have measurable disease based on RECIST.
6. Subject must have completed the last dose of any broad spectrum antibiotic at least 30 days prior to first dose.
7. Subject has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1.
8. Subject has adequate hematologic reserves, measured within 10 days prior to start of study treatment
9. Subject has adequate hepatic function
10. Subject has adequate renal function
11. Subject has recovered from the effects of any prior chemotherapy, immunotherapy, other prior systemic anticancer therapy, radiotherapy, or surgery
12. Subject who has received standard or investigational agents must wait at least 5 half-lives or 4 weeks, whichever is shorter, before enrollment into the study or 4 weeks if the half-life of the investigational agent is not known.
13. Subject who has received wide-field radiotherapy must have completed at least 4 weeks before starting study drug or subject who has received focal radiation must be completed at least 2 weeks before starting study drug.
14. Women of childbearing potential (WOCBP) must have a negative pregnancy test within 7 days of the start of treatment and also on Day 1 before the first dose is administered.
15. Subject meets contraceptive requirements defined in Section 8.4.2. |
1. El sujeto tiene 18 años o más.
2. El sujeto o su representante legal proporcionan su consentimiento informado por escrito.
3. Para la fase 1, el sujeto debe tener un tumor sólido avanzado (incluido un linfoma) y enfermedad progresiva siguiendo al menos 1 línea de tratamiento.
4. Para la fase 2, el sujeto debe tener uno de los siguientes tipos de tumor o histología específica:
• Cohorte de CPCNP: sujetos con CPCNP en fase IIIB o IV que hayan recibido tratamiento con inhibidores de punto de control con enfermedad estable o en mejoría y con evolución de más de 120 días tras el inicio de la terapia con inhibidores de punto de control.
• Cohorte de CCECC: sujetos con CCECC recurrente o metastásico con evolución de la enfermedad durante la quimioterapia o después de ella y que no hayan recibido terapia de inhibidores de punto de control previa.
• Cohorte de tumor de células escamosas agnóstico: sujetos con carcinoma recurrente o metastásico de células escamosas después de recibir quimioterapia y que no hayan recibido terapia de inhibidores de punto de control previa. Los pacientes con CCECC deben inscribirse en la cohorte de CCECC si cumplen estos criterios de aptitud.
• Cohorte de CHC: sujetos con CHC recurrente o metastásico con evolución de la enfermedad durante o después de la terapia antineoplásica y que no hayan recibido terapia de inhibidores de punto de control previa.
• Cohorte de CPCP: sujetos con CPCP inoperable o metastásico con evolución de la enfermedad durante o después de un mínimo de 4 ciclos de quimioterapia y que puede haber incluido una terapia de inhibidores de punto de control de mantenimiento. Los sujetos que hayan recibido terapia con inhibidores de punto de control previa, cuya enfermedad fuera estable o en mejoría y con evolución posterior, son aptos siempre que la evolución se produzca durante más de 120 días tras el inicio de la terapia con inhibidores de punto de control.
5. La enfermedad del sujeto debe ser medible conforme a RECIST.
6. El sujeto debe haber completado la última dosis de cualquier antibiótico de espectro amplio durante al menos 30 días antes de la primera dosis.
7. El sujeto debe tener una puntuación de 0 o 1 en la Escala de valoración del Grupo Oncológico Cooperativo del Este (ECOG PS).
8. El sujeto debe tener reservas hematológicas adecuadas medidas dentro de los 10 días previos al inicio del tratamiento del estudio.
9. El sujeto debe tener una función hepática adecuada.
10. El sujeto debe tener una función renal adecuada.
11. El sujeto se debe haber recuperado de los efectos de cualquier quimioterapia, inmunoterapia, radioterapia, cirugía u otros tratamientos sistémicos contra el cáncer anteriores.
12. El sujeto que haya recibido agentes estándar o de investigación debe esperar al menos 5 semividas o 4 semanas, el período que sea más corto, para poder inscribirse en el estudio, o 4 semanas si la semivida del agente de investigación es desconocida.
13. El sujeto que haya recibido radioterapia de campo extendido debe haber completado al menos 4 semanas antes de empezar con el fármaco del estudio; el sujeto que haya recibido radiación focalizada debe haberla completado al menos 2 semanas antes de empezar con el fármaco del estudio.
14. Las mujeres en edad fértil (MEF) deben obtener un resultado negativo en una prueba de embarazo dentro de los 7 días anteriores al inicio del tratamiento y también el día 1 antes de la administración de la primera dosis.
15. El sujeto debe cumplir los requisitos anticonceptivos establecidos en la sección 8.4.2. |
|
| E.4 | Principal exclusion criteria |
1. Subject is currently pregnant or breastfeeding or is planning to become pregnant during the study period.
2. Subject is employed by Alkermes, Syneos Health, the Investigator, the study center or other affiliate of this study
3. Subject has an active infection or a fever ≥38.5°C (≥101°F) within 3 days of the first scheduled day of dosing for the monotherapy lead-in or Cycle 1 of Phase 2.
4. Subject has known hypersensitivity (Grade ≥3) to any components of ALKS 4230, to pembrolizumab, or any of its excipients.
5. Subjects with mean QT interval corrected by the Fridericia Correction Formula values of >470 msec (in females) or >450 msec (in males) following a standard 12-lead electrocardiogram (ECG); subjects who are known to have congenital prolonged QT syndromes; or subjects who are on medications known to cause prolonged QT interval on ECG.
6. Subject has developed autoimmune disorders while on prior immunotherapy
7. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
8. Subject has active or symptomatic central nervous system metastases unless the metastases have been treated by surgery and/or radiation therapy, the subject has been tapered to a dose of 10 mg or less of corticosteroids for at least 2 weeks before the first dose, and the subject is neurologically stable.
9.Subject has an active autoimmune disease that has required systemic treatment in the past2 years
10. Subject is known to be positive for human immunodeficiency virus and/or history of hepatitis B, or C infections
11.Subject requires pharmacologic doses of corticosteroids (greater than 10 mg ofprednisone daily, or equivalent);
12.Subject has had a second malignancy within the previous 3 years.
13.Subject has any other concurrent uncontrolled illness, including mental illness orsubstance abuse, which may interfere with the ability of the subject to cooperate and participate in the study.
14.Subject has received a live vaccine within 30 days of planned start of study therapy.
15.Subject has active uncontrolled coagulopathy. |
1. El sujeto está actualmente embarazada o en lactancia, o tiene planeado quedar embarazada durante el periodo del estudio.
2. El sujeto es empleado de Alkermes, Syneos Health, el investigador, el centro del estudio o cualquier otra filial de este estudio.
3. El sujeto tiene una infección activa o fiebre ≥38,5 °C dentro de los 3 días anteriores al primer día programado para la administración de la dosis del periodo inicial de la monoterapia o del ciclo 1 de la fase 2.
4. El sujeto tiene hipersensibilidad conocida (Grado ≥3) a cualquier componente de ALKS 4230, al pembrolizumab o a cualquiera de sus excipientes.
5. Los sujetos tienen un intervalo QT medio corregido según los valores de la fórmula de corrección de Fridericia superior a 470 ms (en los sujetos de sexo femenino) o 450 ms (en los sujetos de sexo masculino) después de una electrocardiografía (ECG) de 12 derivaciones estándar; los sujetos tienen síndrome de QT prolongado congénito confirmado; o los sujetos reciben medicación que causa un intervalo QT prolongado, confirmado mediante una electrocardiografía.
6. El sujeto ha desarrollado trastornos autoinmunes durante una inmunoterapia anterior.
7. Los sujetos se deben haber recuperado de todas las toxicidades relacionadas con la radiación, no deben necesitar corticosteroides y no deben haber sufrido neumonitis por radiación.
8. El sujeto tiene metástasis del sistema nervioso central activa o sintomática, a menos que dicha metástasis se haya tratado con cirugía o radioterapia, que se haya reducido la dosis del sujeto a 10 mg o menos de corticosteroides durante al menos 2 semanas antes de la primera dosis y que el sujeto sea neurológicamente estable.
9. El sujeto tiene una enfermedad autoinmune activa que ha requerido un tratamiento sistémico en los últimos 2 años.
10. El sujeto tiene un diagnóstico positivo confirmado de virus de inmunodeficiencia humana, o antecedentes de hepatitis B o C.
11. El sujeto requiere dosis farmacológicas de corticosteroides (más de 10 mg de prednisona a diario, o equivalente);
12. El sujeto ha tenido una segunda neoplasia maligna dentro de los 3 años anteriores.
13. Sujetos con cualquier otra enfermedad no controlada concomitante, incluida enfermedad mental o abuso de sustancias, que pudiera interferir con su capacidad de colaborar y participar en el estudio.
14. El sujeto ha recibido una vacuna viva dentro de los 30 días anteriores al inicio previsto de la terapia del estudio.
15. El sujeto tiene una coagulopatía activa no controlada. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- The incidence and severity of treatment-emergent AEs (Phase 1 and Phase 2)
- ORR based on RECIST 1.1 (Phase 2) |
• la incidencia y gravedad de los AA derivados del tratamiento (fase 1 y fase 2)
• TRO basada en RECIST 1.1 (fase 2) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Treatment-emergent AEs will be evaluated during every visit at the clinic.
Antitumor activity will be determined by the measurement of extent of known disease at baseline and approximately every 9 weeks. After Cycle 10, this should be reduced to every 12 weeks. |
Los acontecimientos adversos derivados del tratamiento (AADT) se evaluarán en cada visita al centro.
Se determinará la actividad antineoplásica según la medición del alcance de la enfermedad conocida al inicio y aproximadamente cada 9 semanas. Después del ciclo 10, este periodo se reducirá a 12 semanas. |
|
| E.5.2 | Secondary end point(s) |
- The incidence of DLTs from the first dose through the end of the DLT observation period (Phase 1)
- Serum concentrations of ALKS 4230 and descriptive PK parameters using noncompartmental analysis (Phase 1)
- Detection of presence of anti-ALKS 4230 antibodies in serum (Phase 1)
- Numbers of circulating cluster of differentiation (CD)8 T cells, T regulatory cells (Tregs), and natural killer cells in peripheral blood (Phase 1)
- Serum levels of interleukin-6 and other cytokines (Phase 1)
- ORR, Disease Control Rate (DCR), Duration of Response (DOR), Time to Response (TTR),and Progression-free Survival (PFS) per RECIST 1.1 (Phase 1)
- Immune ORR (iORR), immune DCR (iDCR), immune DOR (iDOR), immune TTR (iTTR), and immune PFS (iPFS) per Immune RECIST (iRECIST) (Phase 1)
- DCR, DOR, TTR, and PFS, per RECIST 1.1 (Phase 2)
- iORR, iDCR, iDOR, iTTR, and iPFS, per iRECIST (Phase 2)
- Overall Survival (OS) (Phase 2) |
• la incidencia de las TLD desde la primera dosis hasta el final del periodo de observación de la TLD (fase 1);
• las concentraciones séricas de ALKS 4230 y los parámetros de FC descriptivos mediante análisis no compartimentales (fase 1);
• detección de presencia de anticuerpos anti-ALKS 4230 en suero (fase 1);
• los números de células T de cúmulo de diferenciación (CD) 8 circulantes, linfocitos T reguladores (Tregs) y linfocitos citolíticos naturales en la sangre periférica (fase 1);
• las concentraciones séricas de interleuquina-6 y otras citocinas (fase 1);
• TRO, tasa de control de la enfermedad (TCE), duración de la respuesta (DR), tiempo de respuesta (TR) y supervivencia sin progresión (SSP) según RECIST 1.1 (fase 1);
• TRO inmunitaria (TROi), TCE inmunitaria (TCEi), DR inmunitaria (DRi), TR inmunitaria (TRi) y SSP inmunitaria (SSPi) según las directrices RECIST inmunitarias (RECISTi) (fase 1);
• TCE, DR, TR y SSP, según RECIST 1.1 (fase 2);
• TROi, TCEi, DRi, TRi y SSPi, según RECISTi (fase 2);
• Supervivencia total (ST) (fase 2) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Serum samples for evaluation of ALKS 4230 PK and patient immunogenicity will be obtained from each subject at predetermined time points.
Antitumor activity will be determined by the measurement of extent of known disease at baseline and approximately every 9 weeks. After Cycle 10, this should be reduced to every 12 weeks. |
Se obtendrán muestras de suero de cada paciente para la evaluación de la farmacocinética (FC) y la inmunogenia de ALKS 4230 del paciente en puntos temporales predeterminados.
Se determinará la actividad antineoplásica según la medición del alcance de la enfermedad conocida al inicio y aproximadamente cada 9 semanas. Después del ciclo 10, este periodo se reducirá a 12 semanas. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| grupos secuenciales |
| sequential groups |
|
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| France |
| Germany |
| Korea, Republic of |
| Netherlands |
| Spain |
| Taiwan |
| United Kingdom |
| 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
|
| LVLS |
| Última visita del último paciente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 4 |
| 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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