| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic or locally advanced unresectable solid tumors in following indications: breast carcinoma, castration-resistant prostate carcinoma, non-small cell lung carcinoma, epithelial ovarian carcinoma, endometrial carcinoma, head and neck squamous cell carcinoma, or cholangiocarcinoma |
| Tumores sólidos irresecables metastásicos o localmente avanzados ( en las indicaciones siguientes: carcinoma de mama, carcinoma de próstata resistente a la castración, carcinoma de pulmón no microcítico, carcinoma ovárico epitelial, carcinoma endometrial, carcinoma de cabeza y cuello epidermoide o colangiocarcinoma. |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 100000020935 |
|
| 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 |
| The primary objective of the study is to determine the safety profile of CX-2009, the maximum tolerated dose (MTD) / Recommended Phase 2 Dose (RP2D), and the dose-limiting toxicities (DLTs) of CX-2009, when administered intravenously (IV) every 21 days as monotherapy to subjects with selected advanced or recurrent solid tumors. |
| El objetivo principal del estudio es determinar el perfil de seguridad de CX-2009, la dosis máxima tolerada (DMT)/dosis recomendada para la fase II (DRFII) y las toxicidades limitantes de la dosis (TLD) de CX-2009 cuando se administra por vía intravenosa (i.v.) cada 21 días en monoterapia a pacientes con tumores sólidos seleccionados en estadio avanzado o recidivantes. |
|
| E.2.2 | Secondary objectives of the trial |
Evaluate preliminary efficacy in subjects treated with CX-2009 as monotherapy
Characterize the pharmacokinetics (PK) of CX-2009
Assess the incidence of anti-drug antibody (ADA) formation to CX-2009 |
Evaluar la eficacia preliminar en pacientes tratados con CX-2009 en monoterapia
Caracterizar la farmacocinética (FC) de CX-2009
Evaluar la incidencia de la formación de anticuerpos contra el fármaco (AAF) contra CX-2009 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed diagnosis of any active metastatic or locally advanced unresectable solid tumor. Subjects with advanced or metastatic solid tumors who have disease progression after treatment with available therapies that are known to confer clinical benefit, or who are intolerant to treatment in following indications: breast carcinoma, castration-resistant prostate cancer, non-small cell lung cancer (incl adenocarcinoma and squamous cell subtypes), overian carcinoma, endometrial carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma
2. Agrees to provide tumor tissue, archival, new or recent acquisition confirmed to be available prior to initiation of study drug for performance of correlative tissue and cellular studies from a tumor site not previously irradiated
3. Evaluable or measurable disease for dose escalation part A and measurable disease required for dose expansion cohorts part B
4. Subjects with treated brain metastases are eligible if brain metastases are stable and subject does not require radiation therapy or steroids. Active screening for brain metastases is not required.
5. At least 18 y of age
6. Eastern Cooperative Oncology Group performance status of 0 or 1
7. Anticipated life expectancy of at least 3 months
8. screening lab values must meet following criteria: absolute neutrophil count >=1500µl; platelet count >= 100 x 10³/µl (must not have been transfused within prev. 10 days); hemoglobin >=9.0 g/dL (may have been transfused); serum creatinine <= 1.5 x institution upper limit of normal (ULN); aspartate aminotransferase (AST) <= 2.5xinstitution's ULN; alanine aminotransferase (ALT) <= 2.5x institution's ULN (AST, ALT <5 x ULN if liver metastases); and serum total bilirubin <= 1.5x institutional ULN (total bilirubin must be <=3x institution's ULN in subjects with Gilbert's syndrome)
9. Women of childbearing potential and males must agree to use a highly effective method of contraception prior to study entry, while on study drug and for a period of 50 days following the last treatment; highly effective methods of contraception which result in a low failure rate (ie <1 % per year) when used consistently and correctly include implants, injectables, combined hormonal contraceptives, some IUD's, sexual abstinence or a vasectomized partner - True abstinence, when in line with the preferred and usual lifestyme of the subjects is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. (periodic abstinence and withdrawal are not acceptable methods of contraception)
10. The ability to understand and the willingness to sign a written informed consent document and adhere to study schedule and prohibitions |
1. Diagnóstico confirmado histológicamente de cualquier tumor sólido activo no resecable, metastásico o localmente avanzado. Los sujetos con tumores sólidos avanzados o metastásicos que tienen progresión de la enfermedad después del tratamiento con terapias disponibles que se sabe que confieren beneficio clínico o que son intolerantes al tratamiento en las siguientes indicaciones: carcinoma de mama, cáncer de próstata resistente a la castración y cáncer de pulmón de células no pequeñas (Incluyendo adenocarcinoma y subtipos de células escamosas), carcinoma de ovario, carcinoma de endometrio, carcinoma de células escamosas de cabeza y cuello, colangiocarcinoma.
2. Se acuerda proporcionar tejido tumoral, archivo, adquisición nueva o reciente confirmada para estar disponible antes del inicio del fármaco del estudio para la realización de tejido correlativo y estudios celulares de un sitio de tumor no irradiado previamente
3. Enfermedad evaluable o mensurable para la parte A de la escalada de dosis y enfermedad mensurable necesaria para las cohortes de expansión de dosis, parte B
4. Los sujetos con metástasis cerebrales tratadas son elegibles si las metástasis cerebrales son estables y el sujeto no requiere radioterapia o esteroides. La detección activa de las metástasis cerebrales no es necesaria.
5. Al menos 18 años de edad
6. Estatus de desempeño del Grupo de Oncología Cooperativa Oriental de 0 ó 1
7. Esperanza de vida anticipada de al menos 3 meses
8. Los valores del laboratorio de screening deben cumplir los siguientes criterios: recuento absoluto de neutrófilos> = 1500μl; Recuento de plaquetas> = 100 x 10³ / μl (no debe haber sido transfundido dentro de los 10 días previos); Hemoglobina> = 9,0 g / dl (puede haber sido transfundido); Creatinina sérica <= 1,5 x institución límite superior de la normalidad (LSN); Aspartato aminotransferasa (AST) <= 2,5 x LSN de la institución; Alanina aminotransferasa (ALT) <= 2,5x LSN de la institución (AST, ALT <5 x LSN si metástasis hepáticas); Y la bilirrubina total del suero <= 1.5x ULN institucional (la bilirrubina total debe ser <= 3x LSN de la institución en sujetos con síndrome de Gilbert)
9. Las mujeres en edad fértil y los varones deben estar de acuerdo en utilizar un método altamente eficaz de anticoncepción antes del ingreso al estudio, mientras que en el medicamento del estudio y durante un período de 50 días después del último tratamiento; Métodos anticonceptivos altamente efectivos que resultan en una baja tasa de fracaso (es decir, <1% al año) cuando se usan consistentemente y correctamente incluyen implantes, inyectables, anticonceptivos hormonales combinados, algunos DIU, abstinencia sexual o un compañero vasectomizado. Con la preferencia y la vida habitual de los sujetos se considera un método altamente eficaz sólo si se define como abstenerse de relaciones heterosexuales durante todo el período de riesgo asociado con los tratamientos del estudio. (La abstinencia periódica y la retirada no son métodos aceptables de anticoncepción)
10. La capacidad de comprender y la voluntad de firmar un documento de consentimiento informado por escrito y cumplir con el calendario del estudio y las prohibiciones |
|
| E.4 | Principal exclusion criteria |
1. Neuropathie > grade 1
2. Active chronic corneal disorder, including but not limited to the following: sjogren's syndrome, Fuchs corneal dystropathy (requiring treatment), history of corneal transplantation, active herpetic keratitis, and also active ocular conditions requiring ongoing treatment/monitoring such as wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, presensce of papilledema and acquired monocular vision
3. Serious concurrent illness, including, but not limited to following:
- clinically relevant active infection including known active hepatitis B or C. HIV infection or CMV infection or any other known concurrent infectious disease requiring IV antibiotics within 2 weeks of study enrollment
- history of or current active autoimmune diseases, including but not limited to inflammatory bowel diseases, RA, autoimmune thyroiditis, autoimmune hepatitis, systemic sclerosis, systemic lupus erythematosus, autoimmune vasculitis, autoimmune neuropathies or type 1 insuline dependent diabetes mellitus
- significant cardiac disease such as recent MI (<= 6 months prior to day 1), unstable angina pectoris, uncontrolled congestive heart failure (NY Heart association >class II), uncontrolled hypertension (NCI CTCAE v.4.03 grade 3 or higher), uncontrolled cardiac arrythmias, severe aortic stenosis or >= grade 3 cardiac toxicity following prior chemotherapy
- History of multiple sclerosis or other demyelinating disease, Eaton-Lambert syndrome (para-neoplastic syndrome), history of hemorrhagic or ischemic stroke within the last 6 months, or alcoholic liver disease
- Non-healing wound(s) or ulcer(s) except for ulcerative lesions caused by the underlying neoplasm
- Psychiatric illness/social situations that would limit compliance with study requirements
- Interstitial lung disease irrespective of etiology
4. Advanced or metastatic Stage IV NSCLC subjects with epidermal growth factor receptor or anaplastic lymphoma kinase genomic alterations unless they have progressed on treatment with appropriate targeted therapy, including osimertinib for T790M mutation-positive NSCLC
5. Any other anti-cancer treatment such as chemotherapy, immunotherapy, biochemotherapy, radiotherapy, investigative therapy, or high-dose steroids within 30 days of receiving study drug. Low-dose steroids, luteinizing hormone-releasing hormone, aromatase inhibitors (eg, anastrozole), at doses that have been stable for 30 days are permitted for subjects with CRPC
6. History of severe allergic or anaphylactic reactions to previous monoclonal antibody therapy
7. Prior treatment with maytansinoid-containing drug conjugates
8. Subjects with a previously documented absence of thiol-S-purine methyltransferase activity
9. Unresolved acute toxicity NCI CTCAE v4.03 Grade >1 (or baseline, whichever is greater) from prior anti-cancer therapy. Alopecia and other non-acute toxicities are acceptable
10. History of malignancy that is active within the previous 2 years except for localized cancers that are not related to the current cancer being treated, are considered to have been cured and in the opinion of the Investigator, present a low risk for recurrence, including basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the prostate, cervix or breast
11. Currently receiving anticoagulation therapy with warfarin
12. The subject has undergone major surgery (requiring general anesthesia) within 3 months prior to dosing. Subjects who have undergone major surgery within this time period may be enrolled, if, in the Investigator’s judgment, wound healing has largely resolved
13. Subjects who have received a live vaccine within 1 week prior to the planned first dose of CX-2009 will be excluded
14. Participating in an ongoing clinical study involving treatment with medications, radiation, or surgery
15. Women who are pregnant or breast feeding |
1. Neuropathie > grade 1
2. Active chronic corneal disorder, including but not limited to the following: sjogren's syndrome, Fuchs corneal dystropathy (requiring treatment), history of corneal transplantation, active herpetic keratitis, and also active ocular conditions requiring ongoing treatment/monitoring such as wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, presensce of papilledema and acquired monocular vision
3. Serious concurrent illness, including, but not limited to following:
- clinically relevant active infection including known active hepatitis B or C. HIV infection or CMV infection or any other known concurrent infectious disease requiring IV antibiotics within 2 weeks of study enrollment
- history of or current active autoimmune diseases, including but not limited to inflammatory bowel diseases, RA, autoimmune thyroiditis, autoimmune hepatitis, systemic sclerosis, systemic lupus erythematosus, autoimmune vasculitis, autoimmune neuropathies or type 1 insuline dependent diabetes mellitus
- significant cardiac disease such as recent MI (<= 6 months prior to day 1), unstable angina pectoris, uncontrolled congestive heart failure (NY Heart association >class II), uncontrolled hypertension (NCI CTCAE v.4.03 grade 3 or higher), uncontrolled cardiac arrythmias, severe aortic stenosis or >= grade 3 cardiac toxicity following prior chemotherapy
- History of multiple sclerosis or other demyelinating disease, Eaton-Lambert syndrome (para-neoplastic syndrome), history of hemorrhagic or ischemic stroke within the last 6 months, or alcoholic liver disease
- Non-healing wound(s) or ulcer(s) except for ulcerative lesions caused by the underlying neoplasm
- Psychiatric illness/social situations that would limit compliance with study requirements
- Interstitial lung disease irrespective of etiology
4. Advanced or metastatic Stage IV NSCLC subjects with epidermal growth factor receptor or anaplastic lymphoma kinase genomic alterations unless they have progressed on treatment with appropriate targeted therapy, including osimertinib for T790M mutation-positive NSCLC
5. Any other anti-cancer treatment such as chemotherapy, immunotherapy, biochemotherapy, radiotherapy, investigative therapy, or high-dose steroids within 30 days of receiving study drug. Low-dose steroids, luteinizing hormone-releasing hormone, aromatase inhibitors (eg, anastrozole), at doses that have been stable for 30 days are permitted for subjects with CRPC
6. History of severe allergic or anaphylactic reactions to previous monoclonal antibody therapy
7. Prior treatment with maytansinoid-containing drug conjugates
8. Subjects with a previously documented absence of thiol-S-purine methyltransferase activity
9. Unresolved acute toxicity NCI CTCAE v4.03 Grade >1 (or baseline, whichever is greater) from prior anti-cancer therapy. Alopecia and other non-acute toxicities are acceptable
10. History of malignancy that is active within the previous 2 years except for localized cancers that are not related to the current cancer being treated, are considered to have been cured and in the opinion of the Investigator, present a low risk for recurrence, including basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the prostate, cervix or breast
11. Currently receiving anticoagulation therapy with warfarin
12. The subject has undergone major surgery (requiring general anesthesia) within 3 months prior to dosing. Subjects who have undergone major surgery within this time period may be enrolled, if, in the Investigator’s judgment, wound healing has largely resolved
13. Subjects who have received a live vaccine within 1 week prior to the planned first dose of CX-2009 will be excluded
14. Participating in an ongoing clinical study involving treatment with medications, radiation, or surgery
15. Women who are pregnant or breast feeding 1. Neuropatía> grado 1
2. Trastorno activo crónico de la córnea, incluyendo pero no limitado a: síndrome de sjogren, distrofia corneal de Fuchs (que requiere tratamiento), historia de trasplante de córnea, queratitis herpética activa y también condiciones oculares activas que requieren tratamiento / Relacionada con la degeneración macular que requiere inyecciones intravítreas, la retinopatía diabética activa con edema macular, presencia de papiledema y la visión adquirida monocular
3. Enfermedad concurrente grave, incluyendo pero no limitado a siguiente:
- infección activa clínicamente relevante incluyendo hepatitis B activa o C. infección por VIH o infección por CMV o cualquier otra enfermedad infecciosa concurrente conocida que requiera antibióticos intravenosos dentro de las 2 semanas de la inscripción en el estudio
4. Pacientes con CPNM de estadio IV avanzado o metastásico con alteración genómica del receptor del factor de crecimiento epidérmico o de la linfoma quinasa anaplásica (...) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Dose-limiting toxicities
Study-drug related AEs and AEs leading to discontinuation
Changes from baseline in clinical laboratory results and vital signs |
Toxicidad limitante de la dosis
AE relacionados con el estudio y AEs que conducen a la discontinuación
Cambios desde la línea de base en los resultados de laboratorio clínico y signos vitales |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Administrative interim analyses on safety and efficacy or on PK, immunogenicity, and selected biomarkers may be performed at several times prior to completion of the study in order to facilitate program decisions and to support study presentations or publications |
| Los análisis intermedios administrativos sobre seguridad y eficacia o sobre PK, inmunogenicidad y biomarcadores seleccionados pueden realizarse varias veces antes de la finalización del estudio para facilitar las decisiones del programa y apoyar las presentaciones o publicaciones del estudio |
|
| E.5.2 | Secondary end point(s) |
Objective Response Rate (ORR) is the primary efficacy endpoint
Duration of response (DOR)
Time To Tumor Response (TTR)
Progression-free survival (PFS)
Overall survival (OS)
Characterize the pharmacokinetics (PK) of CX-2009, including the
following analytes:
o Intact CX-2009 (referring to the prodrug form of CX-2009 ± DM4);
o Total CX-2009 (intact and activated forms of CX-2009 ± DM4);
o Total CX-2009-conjugated DM4 (antibody conjugated-DM4);
o Free DM4; and
o S-methyl DM4 (DM4-Me) - a DM4 metabolite with potent cytotoxic
activity |
La Tasa de Respuesta Objetiva (ORR) es el punto final de eficacia primario
Duración de la respuesta (DOR)
Tiempo Hasta La Respuesta Del Tumor (TTR)
La supervivencia sin progresión (PFS)
Supervivencia global (SO)
Caracterizar la farmacocinética (PK) de CX-2009, incluyendo la
siguiente analitica:
O intacto CX-2009 (referido a la forma de profármaco de CX-2009 ± DM4);
O Total CX-2009 (formas intactas y activadas de CX-2009 ± DM4); |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Administrative interim analyses on safety and efficacy or on PK, immunogenicity, and selected biomarkers may be performed at several times prior to completion of the study in order to facilitate program decisions and to support study presentations or publications |
| Administrative interim analyses on safety and efficacy or on PK, immunogenicity, and selected biomarkers may be performed at several times prior to completion of the study in order to facilitate program decisions and to support study presentations or publications |
|
| 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 | Yes |
| 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 | 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 | 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.8.2.4 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
| Germany |
| Netherlands |
| Spain |
| United Kingdom |
| 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
|
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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