| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Small Cell Lung Cancer |
| Cáncer de pulmón de células pequeñas |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lung Cancer |
| Cáncer de pulmón |
|
| 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 | 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1b: To evaluate the safety and tolerability and determine the recommended Phase 2 dose (RP2D) of ALRN-6924 when administered to patients with TP53-mutated extensive disease (ED) small cell lung cancer (SCLC) receiving topotecan as 2nd-line treatment
Phase 2: To evaluate the myelopreservation effects of ALRN-6924 when administered at the RP2D to patients with TP53-mutated ED SCLC undergoing 2nd-line treatment with topotecan |
Fase 1b:Evaluar la seguridad y la tolerabilidad y determinar la dosis recomendada para la Fase II (RP2D) de ALRN-6924 cuando se administra a pacientes con cáncer de pulmón de células pequeñas (SCLC) como enfermedad extendida (ED) mutado en TP53 que reciben topotecán como tratamiento de 2ª linea
Fase 2: Evaluar los efectos de mielopreservación de ALRN-6924 cuando se administra a la RP2D a pacientes con SCLC ED mutado en TP53 sometidos a un tratamiento de 2ª línea con topotecán |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1b:
- To evaluate the preliminary myelopreservation effects of ALRN-6924 when administered to patients with TP53-mutated ED SCLC undergoing 2nd-line treatment with topotecan
- To evaluate the efficacy of topotecan when administered as 2nd-line treatment for patients with TP53-mutated ED SCLC who are receiving supportive treatment with ALRN-6924
- To evaluate the pharmacokinetic (PK) profile of ALRN 6924 when administered with topotecan
Phase 2:
- To further evaluate the safety and tolerability of ALRN-6924 as supportive care during treatment with topotecan
- To further evaluate the efficacy of topotecan when administered as 2nd-line treatment for patients with TP53-mutated ED SCLC who are receiving supportive treatment with ALRN-6924
- To further evaluate the PK profile of ALRN 6924 when administered with topotecan |
Fase 1b:
•Evaluar los efectos preliminares de mielopreservación de ALRN-6924 cuando se administra a pacientes con SCLC ED mutado en TP53 sometidos a un tratamiento de 2ª línea con topotecán
•Evaluar la eficacia de topotecán cuando se administra como tratamiento de 2ª línea a pacientes con SCLC ED mutado en TP53 que reciben ALRN-6924 como tratamiento complementario.
•Evaluar el perfil farmacocinético (PK) de ALRN-6924 cuando es administrado conjuntamente con topotecán
Fase 2:
•Evaluar en profundidad la seguridad y la tolerabilidad de ALRN-6924 como tratamiento complementario durante el tratamiento con topotecán
•Evaluar en profundidad la eficacia de topotecán cuando se administra como tratamiento de 2ª línea a pacientes con SCLC ED mutado en TP53 que reciben ALRN-6924 como tratamiento complementario.
•Evaluar el perfil farmacocinético (PK) de ALRN-6924 cuando es administrado conjuntamente con topotecán |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males and females age 18 years or older.
2. Ability to understand the requirements of this clinical trial and willingness to provide written informed consent
3. Histopathological confirmation of ED SCLC that has recurred or been refractory to one line of treatment with standard platinum-based chemotherapy or immuno-chemotherapy. Patients who received immunotherapy after platinum-based chemotherapy remain eligible.
4. Mutated TP53: no wild type (WT) TP 53 gene copies within the tumor (i.e., biallelic mutation, biallelic deletion, or mutation/deletion), as assessed by next generation sequencing (NGS)
5. Measurable disease using RECIST 1.1
6. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
7. Adequate hematological status:
a. absolute neutrophil count (ANC) ≥1500/L
b. platelet count ≥100,000/L
c. hemoglobin ≥9.0 g/dL
8. Adequate hepatic and renal function:
a. total bilirubin ≤1.5 X upper limit of normal (ULN) or ≤ 3 X ULN in the presence of Gilbert syndrome or liver metastases
b. alkaline phosphatase (ALP), aspartate aminotransferase (AST [SGOT]), and alanine aminotransferase (ALT [SGPT]) ≤ 2.5 X ULN in
the absence of liver metastases
c. ALP, AST (SGOT), and ALT (SGPT) ≤5 X ULN in the presence of liver metastases
d. serum creatinine <1.5 X ULN or calculated creatinine clearance ≥ 40 mL/min (C&G or EDTA)
9. Recovery from the acute toxic effects of all prior therapies to Grade ≤1
10. The shorter of 5 half-lives or 4 weeks must have elapsed since any prior systemic therapy, unless no drug-drug interactions with study treatment would be anticipated and the patient had unequivocal radiologic disease
progression during the prior line of therapy.
11. Males and female patients of child-bearing potential must agree to use an acceptable method of birth control for the duration of study treatment and for 3 months (male patients with female partner of child-bearing potential) or 6 months (female patients of child-bearing potential) following the last dose of study treatment. |
1.Hombres y mujeres de más de 18 años.
2.Capaces de entender los requisitos de este ensayo clínico y dispuestos a firmar un consentimiento informado escrito.
3.Confirmación histopatológica de SCLC ED que haya reaparecido o haya mostrado ser resistente a una línea de tratamiento con quimioterapia estándar de platino o inmunoquimioterapia. Los pacientes que recibieron inmunoterapia después de la quimioterapia de platino siguen siendo aptos.
4.TP53 mutado: ausencia de copias del gen TP53 de tipo salvaje dentro del tumor (por ejemplo, mutación bialélica, deleción bialélica o mutación/deleción), evaluada según la secuenciación de próxima generación (NGS)
5.Enfermedad medible utilizando RECIST 1.1
6.Calidad de vida del paciente 0-2 de la Escala ECOG de Eastern Cooperative Oncology Group
7.Estado hematológico adecuado:
a.recuento absoluto de neutrófilos (ANC) ≥1500/L
b.recuento de plaquetas ≥100,000/L
c.hemoglobina ≥9.0 g/dl
8.Función renal y hepática adecuada:
a.bilirrubina total ≤1.5 X límite superior de lo normal (ULN) o ≤ 3 X ULN en presencia de síndrome de Gilbert o metástasis en hígado
b.fosfatasa alcalina (ALP), aspartato aminotransferasa (AST [SGOT]), y alanina aminotransferasa (ALT [SGPT]) ≤ 2.5 X ULN en ausencia de metástasis en hígado
c.ALP, AST (SGOT), y ALT (SGPT) ≤5 X ULN en presencia de metástasis en hígado
d.creatinina sérica <1.5 X ULN o aclaramiento de creatinina calculado ≥ 40 ml/min (C&G o EDTA)
9.Recuperación de los efectos tóxicos agudos de todos los tratamientos anteriores a Grado ≤1
10.Deben haber transcurrido 5 semividas o 4 semanas, lo que antes suceda, desde cualquier tratamiento sistémico anterior, salvo que no se prevean interacciones medicamentosas con el tratamiento de estudio y que el paciente presente una progresión radiológica inequívoca de la enfermedad durante la la línea de tratamiento anterior.
11.Los/las pacientes en edad potencialmente fértil deben aceptar el uso de un método anticonceptivo aceptable durante la completa duración del tratamiento de estudio y durante los 3 meses (pacientes masculinos con pareja femenina en edad fértil) o 6 meses (pacientes femeninas en edad fértil) siguientes a la última dosis del tratamiento de estudio. |
|
| E.4 | Principal exclusion criteria |
1. Known hypersensitivity to any component of study treatment including mannitol, which is an excipient in topotecan.
2. More than one line of prior chemotherapy for ED SCLC (prior immunotherapy is permitted, concurrent with or subsequent to firstline chemotherapy). Previous treatment with platinum-based chemotherapy concomitant with radiotherapy for limited disease is allowed if completed at least one year prior to enrollment into the current trial.
3. Presence of active central nervous system metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable, with no evidence of radiographic or neurologic progression during the screening period and no requirement for steroids for at least 15 days before enrollment.
4. Uncontrolled intercurrent illness including but not limited to:
a. Clinically significant, active, uncontrolled infection including human immunodeficiency virus (HIV), or hepatitis B or C
i. Patients with HIV must be on effective antiretroviral therapy for ≥ 4 weeks prior to enrollment and have HIV viral load < 400 copies/µL, have had no acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the past 12 months, and have CD4+ count ≥ 350 cells/µL.
ii. Patients with chronic hepatitis B virus (HBV) must be on antiviral therapy and have HBV viral load below the limits of detection.
iii. Patients with hepatitis C virus (HCV) must be on or have completed antiviral therapy and have an HCV viral load below the limits of detection.
b. Uncontrolled hypertension
c. Uncontrolled diabetes mellitus
5. Clinically significant electrolyte abnormalities
6. Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling temporary pacemaker
7. History of prior malignancy; patients with a known malignancy that does not affect overall well-being and ability to participate in the study can be considered in consultation with the Medical Monitor.
8. Pregnant or lactating women
9. Hereditary angioedema of any severity or severe or life-threatening angioedema due to any cause.
10. Major surgery within 28 days of enrollment.
11. Significant weight loss (≥15% body weight) within the 4 weeks prior to enrollment.
12. Treatment with an investigational agent for any indication within the shorter of 14 days or 5 half-lives, if the half-life is known
13. The required use of any concomitant medications that are predominantly cleared by hepatobiliary transporters, organic anion transporter polypeptide [OATP] members OATP1B1 and OATP1B3 on the day of the first ALRN-6924 infusion to within 48 hours after the last ALRN-6924 infusion in a treatment cycle
14. Other medications, severe acute/chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study |
1.Hipersensibilidad conocida a uno de los componentes del tratamiento de estudio, incluido el manitol, que es un excipiente del topotecán.
2.Más de una línea de quimioterapia anterior para SCLC ED (se permite una anterior inmunoterapia, concurrente con la quimioterapia de primera línea o subsiguiente). Se permite un tratamiento previo con quimioterapia de platino concomitante con radioterapia para enfermedad limitada siempre que se haya completado al menos un año antes de la participación en este ensayo.
3.Presencia de metástasis en el sistema nervioso central y/o meningitis carcinomatosa. Podrán participar pacientes con metástasis en cerebro previamente tratadas siempre y cuando estén estables, no presenten evidencias de progresión radiográfica o neurológica durante el período de selección y no hayan tomado esteroides durante al menos 15 días antes de la participación.
4.Enfermedad intercurrente no controlada, entre otras:
a.Infección no controlada clínicamente relevante y activa, incluido el virus de inmunodeficiencia humana (VIH), o hepatitis B o C.
i.Los pacientes con VIH deben haber seguido un tratamiento antirretroviral eficaz durante ≥ 4 semanas antes de la participación y tener una carga viral VIH < 400 copias/µl, no haber tenido infecciones oportunistas definitorias del síndrome de inmunodeficiencia adquirida (SIDA) durante los últimos 12 meses, y tener un recuento CD4+ ≥ 350 células/µl.
ii.Los pacientes con hepatitis B crónica (HBV) deben estar siguiendo un tratamiento antiviral y tener una carga viral de HBV por debajo de los límites de detección.
iii.Los pacientes con el virus de la hepatitis C (HCV) deben estar siguiendo o deben haber completado un tratamiento antiviral y tener una carga viral de HCV por debajo de los límites de detección.
b.Hipertensión no controlada
c.Diabetes mellitus no controlada
5.Anomalías en los electrólitos clínicamente relevantes
6.Enfermedad cardíaca clínicamente inestable, incluida la fibrilación auricular inestable, bradicardia sintomática, insuficiencia cardíaca congestiva inestable, isquemia miocárdica activa o marcapasos transitorios y permanentes
7.Historial de una neoplasia anterior; podrán considerarse a pacientes con una neoplasia conocida que no afecte al bienestar general ni a la capacidad de participar en el estudio, previa consulta con el Supervisor Médico.
8.Mujeres embarazadas o en período de lactancia
9.Angioedema hereditario de cualquier gravedad o angioedema severo o potencialmente mortal, con independencia de su causa.
10.Cirugía mayor en el plazo de los 28 días siguientes a la participación.
11.Importante pérdida de peso (≥15 % del peso corporal) durante las 4 semanas anteriores a la participación.
12.Tratamiento con un fármaco experimental para cualquier indicación durante 14 días o 5 semividas, lo que suceda antes, siempre y cuando se conozca la semivida.
13.El uso necesario de medicamentos concomitantes que sean eliminados predominantemente por transportadores hepatobiliares, polipéptidos transportadores de aniones orgánicos [OATP] OATP1B1 y OATP1B3 desde el día de la primera perfusión de ALRN-6924 hasta las 48 horas siguientes a la última perfusión de ALRN-6924 en un ciclo de tratamiento
14.Otros medicamentos, enfermedades médicas o psiquiátricas agudas severas/crónicas, o anomalías en laboratorio que puedan incrementar el riesgo relacionado con la participación en el estudio o la administración del fármaco de estudio, o que puedan interferir en la interpretación de los resultados del estudio y que, en opinión del investigador, impiden la participación del paciente en este estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b: Proportion of patients with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 3/4 treatment emergent adverse events (TEAEs)
Phase 2: Proportion of patients with Grade ≥ 3 neutropenia in Cycle 1 |
Fase 1b:Proporción de pacientes con eventos adversos emergentes del tratamiento (TEAEs) Grado 3/4 según los Criterios Comunes de Terminología para Eventos Adversos (CTCAE) del National Cancer Institute (NCI)
Fase 2: Proporción de pacientes con neutropenia de Grado 3 o 4 en el Ciclo 1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1b: Dose Limiting Toxicity
Phase 2: Cycle 1 |
Fase 1b: Toxicidad Limitante de dosis
Fase 2: Ciclo 1 |
|
| E.5.2 | Secondary end point(s) |
Phase 1b: Proportion of patients with Grade ≥ 3 neutropenia in Cycle 1
Phase 2:
- Proportion of patients with Grade ≥ 3 neutropenia in Cycle 2 and beyond
- Time to first incidence of Grade ≥ 3 neutropenia
- Duration of Grade ≥ neutropenia
- Proportion of patients with Grade ≥ 3 thrombocytopenia
- Proportion of patients with febrile neutropenia
- Proportion of planned treatment cycles delayed due to toxicity
- Proportion of patients with NCI CTCAE Grade 3/4 TEAEs
- ORR
- PFS
- OS
- PK parameters (e.g., AUC, Cmax, tmax, t1/2) of ALRN-6924 |
Fase 1b: Proporción de pacientes con neutropenia de Grado 3 o 4 en el Ciclo 1
Fase 2:
•Proporción de pacientes con neutropenia de Grado 3 o 4 en el Ciclo 2 y más allá
•Proporción de pacientes con trombocitopenia de Grado 3 o 4
•Proporción de pacientes con neutropenia febril
•Proporción de ciclos de tratamiento programados retrasados debido a la toxicidad
•proporción de pacientes con TEAEs Grado 3/4 según los CTCAE del NCI
•ORR
•PFS
•OS
•Parámetros farmacocinéticos (PK) (por ejemplo, AUC, Cmax, tmax, t1/2) de ALRN-6924 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1b: Cycle 1
Phase 2: Cycle 2 and beyond |
Fase 1b: Ciclo 1
Fase 2: Ciclo 2 y posteriores |
|
| 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 | 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 | 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 |
| safety and tolerability |
| Seguridad y tolerabilidad |
|
| 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 | 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 |
| Topotecan más ALRN-6924 vs Topotecan sin ALRN-6924 |
| Topotecan plus ALRN-6924 vs Topotecan without ALRN-6924 |
|
| 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
| 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 | 9 |
| 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 |
| Bosnia and Herzegovina |
| Croatia |
| Germany |
| Netherlands |
| Poland |
| Serbia |
| Spain |
| United States |
|
| 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
|
Patients will be followed for overall survival until death, or study completion
or termination by the Sponsor. |
| Los pacientes serán seguidos para supervivencia global hasta la muerte o la finalización del estudio o terminación por parte del Promotor. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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