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A phase I/II, open-label, multi-center study of the safety and efficacy of BLZ945 as single agent and in combination with PDR001 in adults patients with advanced solid tumors - CBLZ945X2101

Studio Clinico

Patologia: Neoplasie della mammella, Neoplasie cerebrali, Neoplasie del polmone, Carcinoma del pancreas esocrino

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: No

Fase di studio: I, II

Richiesta mandatoria di tessuto: 

Linee di trattamento: Seconda linea, Terza/N linea

Criteri di inclusione: 

1. Written informed consent must be obtained prior to any screening procedures.
2. Age ≥ 18 years
3. Phase I part: Patients with advanced/metastatic solid tumors, with measurable or unmeasurable disease as determined by RECIST v1.1 (refer to Appendix 1) or RANO (glioblastoma), who have progressed despite standard therapy or are intolerant of standard therapy, or for whom no standard therapy exists.
4. Patients must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution’s guidelines. Patients must be willing to undergo a new tumor biopsy at screening, and during treatment. Exceptions may be considered for glioblastoma patients after documented discussion with Novartis.
5. Phase II part: Patients with advanced/metastatic tumors in the below selected indications, with at least one measurable lesion as determined by RECIST v1.1 or RANO (glioblastoma)
    - advanced pancreatic cancer who failed to respond or progressed on or after treatment with standard of care
    - advanced triple negative breast cancer, who failed to respond to standard treatment or progressed on or after standard treatment
    - recurrent glioblastoma (GBM) who failed to respond or progressed on radiotherapy and temozolomide except for patients with O6-methylguanine-DNA methyltransferase (MGMT) unmethylated newly diagnosed GBM who may have received radiation therapy only.
6. Patient Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
7. Life expectancy more than 12 weeks.

Criteri di esclusione: 

Patients eligible for this study must not meet any of the following criteria:
1. Presence of symptomatic CNS metastases, or CNS metastases that require local CNSdirected therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids within the prior 2 weeks before start of study treatment. Patients with treated brain metastases should be neurologically stable (for 4 weeks post-treatment and prior to study enrollment) and off of steroids for at least 2 weeks before administration of any study drug (this exclusion criteria does not apply for GBM patients)
2. History of severe hypersensitivity reactions to study drugs(s) and other monoclonal antibodies and/or their excipients.
3. Having out of range laboratory values defined as:
    - Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 40 mL/min or serum creatinine >1.5 x Upper Limit of Normal (ULN)
    - Total bilirubin > 1.5 x ULN, except for patients with Gilbert’s syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
    - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 x ULN,
    - Absolute neutrophil count (ANC) < 1.0 x 109/L
    - Platelet count < 75 x 109/L
    - Hemoglobin < 9 g/dL
4. Impaired cardiac function or clinically significant cardiac disease, including any of the following:
    - Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA grade ≥ 2), uncontrolled hypertension or clinically significant arrhythmia
    - QTcF >470 msec on screening electrocardiogram (ECG) or congenital long QT syndrome
    - Acute myocardial infarction or unstable angina pectoris < 3 months prior to study entry
5. Known human immunodeficiency virus (HIV), active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection. No testing is required at screening. Patients whose HBV or HCV infection is controlled by antiviral therapy should not be excluded.
6. Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type.
7. Any medical condition that would, in the investigator’s judgment, prevent the patient’s participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results, including but not limited to:
    - ongoing symptomatic interstitial lung disease (ILD), noninfectious pneumonitis or history of drug induced interstitial lung disease
8. Active autoimmune disease or a documented history of autoimmune disease, including ulcerative colitis and Crohn’s disease or any condition that requires systemic steroids, except vitiligo or resolved asthma/atopy that is treated with broncho-dilators (e.g.
albuterol). Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately treated for skin rash or with replacement therapy for endocrinopathies should not be excluded.
9. Systemic steroid therapy or any immunosuppressive therapy (≥10mg/day prednisone or equivalent). Topical, inhaled, nasal and ophthalmic steroids are not prohibited. For GBM patients only: patients must not be receiving greater than 1 mg dexamethasone per day (or an equivalent amount of an alternative corticosteroid) (Kostaras et al, 2014).
10. Use of any vaccines against infectious diseases (e.g. varicella, pneumococcus) within 4 weeks of initiation of study treatment.
11. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity, e.g. mitomycin C and nitrosoureas, 4 weeks is indicated as washout period. Prior antibodies or immunotherapies require a 4 weeks washout period.
12. Major surgery within 2 weeks of the first dose of study treatment (mediastinoscopy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery).
13. Pre-treatment with anti-cytotoxic T-Lymphocyte-associated protein 4 (CTLA-4) antibodies in combination with any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathway. Patients pre-treated with anti-CTLA-4 as single agent must have minimum 8 week washout period between the last dose of anti-CTLA-4 and the first dose of PDR001.
14. Participation in an interventional, investigational non-immunotherapy study within 2 weeks of the first dose of study treatment.
15. Presence of ≥ common terminology criteria for adverse events (CTCAE) grade 2 toxicity (except alopecia, peripheral neuropathy and ototoxicity, which are excluded if ≥ CTCAE grade 3) due to prior cancer therapy.
16. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF) and thrombopoietin mimetics ≤ 2 weeks prior to start of study drug. An erythroid stimulating agent is allowed as long as it was initiated at least 2 weeks prior to the first dose of study treatment and the patient is on a stable dose.
17. Radiotherapy within 2 weeks of the first dose of study drug, except for palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass. To allow evaluation for response to treatment, patients enrolled in the phase II part must have remaining measurable disease that has not been irradiated.
18. Patient receiving treatment with medications that meet one of the following criteria and that cannot be discontinued at least 1 week prior to start of treatment and for the duration of the study:
    - Strong inhibitors of CYP2C8 and of CYP3A4/5.
    - Strong inducers of CYP2C8 and of CYP3A4/5.
    - Proton pump inhibitors
    - Co-administration of moderate CYP2C8 and of CYP3A4/5 inhibitors
    - Co-administration of moderate CYP2C8 and of CYP3A4/5 inducers
19. 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 human chorionic gonadotropin (hCG) laboratory test.
20. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 14 days after last dose of BLZ945 as a single agent and for 150 days after the last dose of BLZ945 in combination with PDR001. Highly effective contraception methods include:
    - Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptom-thermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
    - Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment.
    - Male sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient.
    - Use of oral (estrogen and progesterone), injected or implanted combined hormonal methods of contraception or placement of an intrauterine device or intrauterine system, or other forms of hormonal contraception that have comparable efficacy (failure rate
<1%), for example hormone vaginal ring or transdermal hormone contraception.
In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age appropriate [generally age from 40 to 59], history of vasomotor symptoms [e.g. hot flush] in the absence of other medical justification) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential
21. Sexually active males unless they use a condom during intercourse while taking the drug during treatment, for 14 days after stopping BLZ945 single agent or for 150 days after stopping BLZ945 in combination with PDR001 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 drug via semen.

Trattamento sperimentale: 

BLZ945 single agent
BLZ945 + PDR001

Trattamento di controllo: 

NA

Obiettivi primari dello studio: 

Phase I: To characterize the safety and tolerability and to estimate the MTDs and/or RP2Ds of BLZ945 as a single agent (in non-Japanese and Japanese patients, separately) and in combination with PDR001
Phase II: To assess the anti-tumor activity of BLZ945 in combination with PDR001 (and BLZ945 as single agent if appropriate)

Obiettivi secondari dello studio: 

Phase I: To assess the pharmacodynamics effect of BLZ945 as single agent and in combination with PDR001
Phase I : To evaluate the preliminary anti-tumor activity of BLZ945 as single agent and in combination with PDR001
Phase II : To evaluate the preliminary anti-tumor activity of BLZ945 as single agent (if appropriate) and in combination with PDR001
Phase II: To describe the survival distribution of patients treated with BLZ945 as single agent if appropriate and in combination with PDR001 for each disease group
Phase I/II parts: Characterize PK of BLZ945 as a single agent and in combination with PDR001
Phase I/II parts: To assess emergence of anti-PDR001 antibodies following one or more i.v. infusions of PDR001 in combination with BLZ945

Centri partecipanti

Nord Italia

Istituto Clinico Humanitas Rozzano
Via Manzoni 56 - 20089 Rozzano - MI

Riferimento: Prof. Armando Santoro
Telefono: 0282244080
Email: armando.santoro@cancercenter.humanitas.it

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2015-005806-12

Data di inserimento: 26.10.2018

Promotore

Novartis

CRO

/

Principal Investigator ITALIA

Istituto Clinico Humanitas - Rozzano

Riferimento: Prof. Armando Santoro

Telefono: 0282244080

Email: armando.santoro@cancercenter.humanitas.it

Localita: Rozzano (Mi)

 

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