Clinical Trials Register

Summary
EudraCT Number:	2016-002001-19
Sponsor's Protocol Code Number:	VHIO-16001
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-06-30
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Belgium - FPS Health-DGM

A.2

EudraCT number

2016-002001-19

A.3

Full title of the trial

A phase II open-label study with the anti-PD-L1 Atezolizumab monoclonal antibody in combination with Bevacizumab in patients with advanced chemotherapy resistant colorectal cancer and MSI-like molecular signature

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Atezolizumab in combination with Beva in advanced CRC with MSI-like molecular signature

A.4.1

Sponsor's protocol code number

VHIO-16001

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02982694

A.5.4

Other Identifiers

Name:

EORTC

Number:

1604-GITCG

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	VHIO
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Horizon 2020
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	F. Hoffmann-La Roche Ltd
B.4.2	Country	Switzerland
B.4.1	Name of organisation providing support	EORTC
B.4.2	Country	Belgium
B.4.1	Name of organisation providing support	VHIO
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	VHIO
B.5.2	Functional name of contact point	Clinical research support unit
B.5.3	Address:
B.5.3.1	Street Address	Calle Natzaret, 115-117
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08035
B.5.3.4	Country	Spain
B.5.4	Telephone number	+3493254 34 50 8614
B.5.6	E-mail	smunoz@vhio.net

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Avastin
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BEVACIZUMAB
D.3.9.1	CAS number	216974-75-3
D.3.9.4	EV Substance Code	SUB16402MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Tecentriq
D.2.1.1.2	Name of the Marketing Authorisation holder	F. HOFFMANN-LA ROCHE LTD
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Atezolizumab
D.3.2	Product code	MPDL3280A
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ATEZOLIZUMAB
D.3.9.3	Other descriptive name	MPDL3280A
D.3.9.4	EV Substance Code	SUB178312
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Colorectal carcinoma

E.1.1.1

Medical condition in easily understood language

Intestinal cancer

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	21.0
E.1.2	Level	PT
E.1.2	Classification code	10061451
E.1.2	Term	Colorectal 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

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to determine the anti-tumor activity, as measured by overall response rate (ORR) of atezolizumab in combination with bevacizumab in patients with chemotherapy resistant CRC and positivity for MSI-like molecular signature.

E.2.2

Secondary objectives of the trial

· To assess anti-tumor activity of atezolizumab combined with bevacizumab as measured by duration of response and time to response, immune-related tumor response, progression free survival (PFS) and overall survival (OS).
· To determine the anti-tumor activity, as measured by ORR of atezolizumab in combination with bevacizumab in the subgroup of patients with chemotherapy resistant CRC and positive for both MSI-like signature and “real MSI” by standard testing – immunohistochemistry (IHC) or PCR.
· To determine the anti-tumor activity, as measured by ORR of atezolizumab in combination with bevacizumab in the subgroup of patients with chemotherapy resistant CRC and positive for MSI-like signature but “MSS” by standard testing.
· To characterize the safety and tolerability of atezolizumab plus bevacizumab as assessed by the incidence and severity of adverse events.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

· Written informed consent must be given according to ICH/GCP and national/local regulations.
· Histological or cytological proof of metastatic CRC.
· Disease progression or relapse after at least one line of treatment for advanced CRC with a fluoropyrimidine containing chemotherapy as single agent or in combination (combinations with oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab are allowed).
· Written documentation of positivity for MSI-like gene signature as determined by Agendia test.
· Unresectable disease, with at least one measurable lesion according to RECIST 1.1.
· Age ≥ 18 years.
· WHO performance status of 0-1.
· Ability and capacity to comply with study and follow-up procedures.
· Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 28 calendar days prior to the first study treatment:
- ANC > 1.5 x 109/L (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1)
- WBC counts > 2500/μL
- Platelet count > 100,000/ μL (without transfusion within 2 weeks prior to Cycle 1, Day 1)
- Hemoglobin > 9.0 g/dL
- AST, ALT, and alkaline phosphatase < 2.5 x ULN, with the following exceptions:
i Patients with documented liver metastases: AST and ALT < 5 x ULN
ii Patients with documented liver or bone metastases: alkaline phosphatase < 5 x ULN
- Bilirubin <1.5 x ULN. Patients with known Gilbert disease who have serum bilirubin level < 3 x ULN may be enrolled.
- PT and PTT <1.5 x ULN, unless on a stable dose of warfarin
- Serum albumin > 2.5 g/dL
- Creatinine clearance > 30 mL/min (Cockcroft-Gault formula or based on 24-hour urine collection)
- Protein < 2+ on dipstick urinalysis or ≤ 1.0 g in a 24-hour urine collection. All patients with ≥2+ protein on dipstick urinalysis at baseline must undergo a 24-hour urine collection for protein.
· Women of child bearing potential (WOCBP) must have a negative serum pregnancy test before registration.
· Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last bevacizumab treatment (for women and men) and 5 months
after the last atezolizumab treatment (for women) . A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
· Female subjects who are breast feeding should discontinue nursing before trial registration and until 6 months after the last bevacizumab treatment and 5 months after the last atezolizumab treatment.

E.4

Principal exclusion criteria

· Any treatment with investigational drugs within 28 d prior to Cycle 1, Day 1.
· Previous cytotoxic agent within 14 d of planed treatment initiation.
· Active or untreated CNS metastases as determined by computed CT or MRI
· Radiotherapy within 14 d prior to Cycle 1, Day 1.
· Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures.
· Previous (within the last 5 y) or concurrent malignancies, with the exception of those treated with expected curative outcome as cone-biopsied in situ carcinoma of the cervix, basal cell carcinoma of the skin, localized prostate cancer or ductal carcinoma in situ of the
breast.
· Life expectancy of < 12 w.
· History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
· Positive test for HIV.
· Active hepatitis B or hepatitis C.
· Active tuberculosis.
· Severe infections within 4 w prior to Cycle 1, Day 1.
· Infection within 2 w prior to Cycle 1, Day 1.
· Received therapeutic oral or IV antibiotics within 2 w prior to Cycle 1, Day 1.
· Significant cardiovascular or cerebrovascular disease
· Major surgical procedure within 28 d prior to cycle 1, day 1, or planned procedure or surgery during the study.
· Prior allogeneic stem cell or solid organ transplant.
· 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.
· Prior treatment with CD137 agonists, anti−CTLA-4, anti−PD-1, or anti−PD-L1 therapeutic antibody or immune-related pathway-targeting agents.
· Current or recent use of dipyridamole, ticlopidine, clopidogrel, or cilostazol .
· Unstable dose in the last 2 w prior to the first study treatment of prophylactic or therapeutic low molecular−weight heparin, direct thrombin inhibitors, or warfarin. Stable dose is permitted where appropriate anticoagulation indices are stable.
· Inadequately controlled hypertension.
· Prior history of hypertensive crisis or hypertensive encephalopathy.
· Significant vascular disease within 6 m prior to Cycle 1, Day 1.
· Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the bevacizumab or atezolizumab formulation.
· Evidence of bleeding diathesis or clinically significant coagulopathy.
· Patients with history of pulmonary hemorrhage/hemoptysis within 6 m prior to Cycle 1, Day 1.
· Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 calendar days prior to the first dose of bevacizumab.
· History of abdominal or tracheoesophageal fistula or gastrointestinal perforation within 6 m prior to Cycle 1, Day 1.
· Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding.
· Evidence of abdominal free air not explained by paracentesis or recent surgical procedure.
· Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture.
· History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome,
Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis:
· Prior allogeneic bone marrow transplantation or prior solid organ transplantation.
· History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
· Administration of a live, attenuated vaccine within 4 w before Cycle 1, day 1
· Treatment with systemic immunostimulatory agents within 4 w or five half-lives of the drug, whichever is longer, prior to study treatment.
· Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 w prior to start of study maintenance treatment, or requirement for systemic immunosuppressive medications during the trial. The use of inhaled corticosteroids and mineralocorticoids is allowed.
· If receiving a RANKL inhibitor, unwilling to adopt alternative
treatment such as bisphosphonates, while receiving atezolizumab.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is overall response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

E.5.1.1

Timepoint(s) of evaluation of this end point

every 9 weeks after C1D1 date

E.5.2

Secondary end point(s)

1. Duration of RECIST response.
2. Time to RECIST response.
3. Immune-related (ir) response rate as measured by irRC with the use of unidimensional measurement.
4. Progression free survival (PFS), defined as time from treatment initiation to progressive disease or death.
5. Overall survival (OS), defined as time from treatment initiation to death.

E.5.2.1

Timepoint(s) of evaluation of this end point

1-4. every 9 weeks after C1D1 date
5. at each visit

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

End of study occurs when all of the following criteria have been satisfied:
· Ninety days after the last patient has stopped protocol treatment
· The trial is mature (i.e. reached the required number of events) for the analysis of the primary endpoint as defined in the protocol.
· The database has been fully cleaned and frozen for this analysis.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

FOLFIRI + biologic vs TAS-102 vs clinical trial

F. Hoffmann-La Roche Ltd will offer continued access to IMPs Bevacizumab and Atezolizumab free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access
to Investigational Medicinal Product.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-07-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-11-24

P. End of Trial
P.	End of Trial Status	Ongoing

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