E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally Advanced and/ or Metastatic Solid Tumors |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065143 |
E.1.2 | Term | Malignant solid tumour |
E.1.2 | System Organ Class | 100000004864 |
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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 |
Part IA:
- safety, tolerability of sequential single-dose (SD) RO7009789 intravenous (IV) and MPDL3280A (here: MPDL)
- safety, tolerability of sequential SD RO7009789 subcutaneous (SC) and MPDL
- single-agent MTD of RO7009789 SC
- preferred route of sequential RO7009789 (IV vs SC) and MPDL
- recommended SC dose of RO7009789 in combo with vaccines
Part IB:
- safety, tolerability of single combo of RO7009789 (IV and SC) and MPDL
- MTD of RO7009789 (IV and SC) in combo with MPDL
- recommended Part II dose of RO7009789 for multiple concomitant treatment with MPDL
- preferred route (IV vs. SC) of RO7009789 in combo with MPDL
Part II:
- safety, tolerability of multiple administrations of RO7009789 (IV or SC) in combo with MPDL
- optimal schedule of RO7009789 in combo with MPDL
- Recommended Phase II Dose of RO7009789 for multiple combo treatment with MPDL
Part III:
- clinical activity of RO7009789 in combo with MPDL in tumor types identified in Part II |
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E.2.2 | Secondary objectives of the trial |
Parts IA,IB:
-PK IV and SC RO7009789 SD (IA) and in combo with MPDL (IB)
-PK MPDL after RO7009789 (IA) and in combo with RO7009789 (IB)
-PD biomarkers of immune-modulatory and anti-tumor activity of RO7009789 SD (IA) and in combo with MPDL (IB)
-PK/PD rel.ships of IV and SC RO7009789 SD (IA) and in combo with MPDL (IB)
-immunogenic potential RO7009789 and/or MPDL by measuring ADA and assessing their relationship with other outcome measures (IA; IB)
-clinical activity RO7009789 in combo with MPDL (IB)
Parts II,III:
-PK multiple dose (MD) RO7009789 in combo with MPDL (II; III)
-PK MD MPDL in combo with RO7009789 (II; III)
-PD biomarker of the immune-modulatory and anti-tumor activity of RO7009789 in combo with MPDL (II; III)
-PK/PD rel.ships RO7009789 and MPDL in a MD setting (II; III)
-immunogenic potential RO7009789 and/or MPDL by measuring ADA and assessing their
relationship with other outcome measures (II; III)
-clinical activity RO7009789 in combo with MPDL (II)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Histologically confirmed diagnosis of locally advanced and/or metastatic solid tumors, which are not amenable to standard therapy
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Life expectancy >/= 16 weeks
- Adequate hematologic and end organ function
- Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
- Ability to comply with the collection of tumor biopsies; tumors must be accessible for biopsy
- Agreement to use effective methods of contraception per the protocol requirements; female patients of childbearing potential must have a negative pregnancy test (urine/serum) within seven days prior to the first study drug administration |
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E.4 | Principal exclusion criteria |
- Diagnosis of non-small cell lung cancer (NSCLC) (excluded from Part I only)
- Any approved anti-cancer therapy that includes chemotherapy, hormonal therapy, or radiotherapy within 2 weeks prior to the first dose of study treatment; the following is, allowed: Palliative radiotherapy for bone metastases </= 2 weeks prior to Cycle 1 Day 1
- Adverse events from prior anti-cancer therapy that have not resolved to </= Grade 1 except for any grade alopecia and </= Grade 2 peripheral neuropathy
- Bisphosphonate therapy for symptomatic hypercalcemia. Use of bisphosphonate therapy for other reasons allowed. Patients receiving denosumab prior to enrollment must be willing to receive a bisphosphonate while on study.
- Uncontrolled pleural effusion, pericardial effusion, or ascites that require recurrent drainage procedures (at least one monthly). Patients with indwelling catheters are allowed.
- Known clinically significant liver disease which includes active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver, and inherited liver disease
- History (within the previous year) of congestive heart failure, stroke, arrhythmia, or myocardial infarction
- History of peripheral venous thrombosis or thromboembolic event (within 12 months prior to Cycle 1 Day 1)
- Significant cardio- or cerebrovascular disease within 6 months prior to Cycle 1 Day 1
- Known hereditary or acquired coagulopathies
- Clinically meaningful proteinuria
- Requiring dialysis
- Known primary CNS malignancy or symptomatic or untreated CNS metastases: patients with asymptomatic-treated CNS metastases may be enrolled after consultation with the Medical Monitor, provided they meet the following criteria:
•Radiographic demonstration of improvement upon completion of CNS-directed therapy and no evidence of interim progression between completion of CNS-directed therapy and the screening radiographic study
•No stereotactic radiation or whole-brain radiation within 28 days prior to Cycle 1 Day 1
- Allergy or hypersensitivity to components of the RO7009789 formulation or to components of MPDL3280A formulation
- History of autoimmune diseases
- History of idiopathic pulmonary fibrosis, pneumonitis (excluding infectious disease-induced), organizing pneumonia, or evidence of active pneumonitis. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- Patients with HIV infection, active hepatitis B (chronic or acute), or hepatitis C infection
- Active tuberculosis
- Severe infections within 4 weeks prior to Cycle 1 Day 1
- Signs or symptoms of infection within 2 weeks prior to Cycle 1 Day 1
- Received oral or IV antibiotics within 2 weeks prior to Cycle 1 Day 1. Patients receiving prophylactic antibiotics are eligible.
- Major surgical procedure within 28 days prior to Cycle 1 Day 1 or anticipation of need for a major surgical procedure during the course of the study
- Administration of a live, attenuated vaccine within 4 weeks before Cycle 1 Day 1 or anticipation that such a live attenuated vaccine will be required during the study
- Malignancies other than disease under study within 3 years prior to Cycle 1 Day 1 with the exception of those with a negligible risk of metastasis or death and with expected curative outcome
- Prior treatment with anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibody
- Previous treatment with any other compound that targets CD40
- Treatment with systemic immunostimulatory agents within 4 weeks or 5 times the half-life of the drug, whichever is shorter, prior to Cycle 1 Day 1
- Treatment with investigational agent within 4 weeks prior to Cycle 1 Day 1 (or within 5 times the half-life of the investigational product, whichever is longer)
- Concomitant treatment with anticoagulants except low dose molecular weight heparin for prophylactic purposes
- Treatment with systemic immunosuppressive medications within 2 weeks prior to Cycle 1 Day 1
- Patients who have received acute, low-dose, systemic immunosuppressant medications may be enrolled in the study after discussion with and approval by the Medical Monitor. The use of inhaled corticosteroids and the use of mineralocorticoids for patients with orthostatic hypotension or adrenocortical insufficiency is allowed.
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
- Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
- Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
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E.5 End points |
E.5.1 | Primary end point(s) |
a) Safety (composite outcome measure): Incidence and severity of adverse events and infusion-related reactions, incidence of autoantibodies, incidence of ADAs; changes in vital signs, physical findings, ECG findings, and clinical laboratory results
b) Incidence and severity of dose-limiting toxicities (DLTs)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
a) - Timeframe: 36 months
b) - Timeframe: 15 months (Part 1)
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E.5.2 | Secondary end point(s) |
c) Pharmacokinetic profile and parameters derived from the concentration-time curve following i.v. infusion of RO7009789 [AUC, Cmax, Cmin, CL, volume of distribution at steady state, half-life] (composite outcome measure)
d) Pharmacokinetic profile and parameters derived from the concentration-time curve following s.c. administration of RO7009789 [AUC, Cmax, time to Cmax (Tmax), Cmin, apparent clearance CL/F, volume of distribution (V/F), t1/2] (composite outcome measure)
e) Pharmacokinetic profile and and parameters derived from the concentration-time curve following i.v. or s.c. administration of RO7009789 [AUC, Cmax, Cmin, volume of distribution at steady state, half-life] (composite outcome measure)
f) Pharmacokinetic profile and parameters derived from the concentration-time curve following IV infusion of MPDL3280A [Cmax, Cmin] (composite outcome measure)
g) Pharmacodynamics: levels of circulating Ki67+ T-cell levels
h) Pharmacodynamics: change in 18F-fluorothymidine (FLT) uptake by spleen
i) Pharmacodynamics: change in CD8+ cells tumor-infiltration levels
k) Pharmacodynamics: PD-L1 expression levels on tumor, immune-filtrating cells
l) Efficacy [Best overall response rate, objective response rate, disease control rate, duration of objective response, progression-free survival] (composite outcome measure)
m) Overall survival
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
c) - Timeframe: 15 months
d) - Timeframe: 15 months
e) - Timeframe: 23 months (Part 2 and Part 3)
f) - Timeframe: 36 months
g) - Timeframe: 36 months
h) - Timeframe: 15 months
i) - Timeframe: 36 months
k) - Timeframe: 36 months
l) - Timeframe: 36 months
m) - Timeframe: From first study treatment to death from any cause, approximately 36 months |
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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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
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 |
first administration of combination of the two IMPs |
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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 | 4 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
Canada |
Denmark |
France |
Netherlands |
Spain |
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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
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Unless it is prematurely terminated by the Sponsor, the study will end once the last patient has completed the 120-day follow-up visit, has died, or has withdrawn consent, whichever occurs first. |
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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 | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |