COVID-19 studies are our top priority. For all other trials, there is a 4-week delay in processing a trial submitted to the ANZCTR and additional delays for updates of registered trials. We appreciate your patience.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03708328




Registration number
NCT03708328
Ethics application status
Date submitted
9/10/2018
Date registered
17/10/2018
Date last updated
10/03/2020

Titles & IDs
Public title
A Dose Escalation and Expansion Study of RO7121661, a PD-1/TIM-3 Bispecific Antibody, in Participants With Advanced and/or Metastatic Solid Tumors
Scientific title
An Open Label, Multicenter, Dose Escalation and Expansion, Phase 1 Study to Evaluate Safety, Pharmacokinetics, and Preliminary Anti-Tumor Activity of RO7121661, a PD-1/TIM-3 Bispecific Antibody, in Patients With Advanced and/or Metastatic Solid Tumors
Secondary ID [1] 0 0
2018-000982-35
Secondary ID [2] 0 0
NP40435
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Solid Tumors 0 0
Metastatic Melanoma 0 0
Non-small Cell Lung Cancer (NSCLC) 0 0
Small Cell Lung Cancer (SCLC) 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lung - Mesothelioma
Cancer 0 0 0 0
Lung - Non small cell
Cancer 0 0 0 0
Lung - Small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - RO7121661

Experimental: Dose Escalation Part A1: Once Every 2 Weeks (Q2W) - RO7121661 will be administered in treatment cycles once every 2 weeks (Q2W). Dose escalation will be carried out according to a modified continual reassessment method (mCRM) with escalation with overdose control (EWOC) design. Dosing on the Q2W schedule will inform whether a once every 3 weeks (Q3W) schedule will be assessed.

Experimental: Dose Escalation Part A2: Once Every 3 Weeks (Q3W) - RO7121661 will be administered in treatment cycles once every 3 weeks (Q3W). Dose escalation will be carried out according to a modified continual reassessment method (mCRM) with escalation with overdose control (EWOC) design.

Experimental: Expansion Part B1: Metastatic Melanoma Cohort - This cohort will comprise participants with checkpoint inhibitor (CPI) experienced, second line and beyond metastatic melanoma. The starting dose of RO7121661 for Expansion will be derived from the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) and the best dosing schedule determined during Dose Escalation.

Experimental: Expansion Part B2: NSCLC Cohort 1 - This cohort will comprise participants with CPI and platinum experienced, second or third line PD-L1 positive non-small cell lung cancer (NSCLC). The starting dose of RO7121661 for Expansion will be derived from the MTD/RDE and the best dosing schedule determined during Dose Escalation.

Experimental: Expansion Part B3: NSCLC Cohort 2 - This cohort will comprise participants with PD-L1 high, cancer immunotherapy (CIT) naïve first line NSCLC. The starting dose of RO7121661 for Expansion will be derived from the MTD/RDE and the best dosing schedule determined during Dose Escalation.

Experimental: Expansion Part B4: SCLC Cohort - This cohort will comprise participants with CPI naïve small cell lung cancer (SCLC) with prior failure of, progression on, or intolerance to, standard therapy. The starting dose of RO7121661 for Expansion will be derived from the MTD/RDE and the best dosing schedule determined during Dose Escalation.


Treatment: Drugs: RO7121661
RO7121661 will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Dose Escalation: Number of Participants with a Dose-Limiting Toxicity (DLT)
Timepoint [1] 0 0
For Part A1 (Q2W: 1 cycle is 14 days): From Cycle 1 Day 1 to Cycle 2 Day 7 (up to 35 days); For Part A2 (Q3W: 1 cycle is 21 days): From Cycle 1 Day 1 to Cycle 2 Day 7 (up to 42 days)
Primary outcome [2] 0 0
Dose Escalation: Maximum Tolerated Dose (MTD) of RO7121661
Timepoint [2] 0 0
Approximately 12 months
Primary outcome [3] 0 0
Number of Participants with at Least One Adverse Event, Severity Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)
Timepoint [3] 0 0
Up to 27 months
Primary outcome [4] 0 0
Number of Participants with Adverse Events Leading to Withdrawal from Study Treatment
Timepoint [4] 0 0
Up to 27 months
Primary outcome [5] 0 0
Objective Response Rate, Assessed According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Timepoint [5] 0 0
Up to 24 months
Primary outcome [6] 0 0
Disease Control Rate, Assessed According to RECIST v1.1
Timepoint [6] 0 0
Up to 24 months
Primary outcome [7] 0 0
Duration of Response, Assessed According to RECIST v1.1
Timepoint [7] 0 0
Up to 24 months
Primary outcome [8] 0 0
Progression Free Survival, Assessed According to RECIST v1.1
Timepoint [8] 0 0
Up to 24 months
Secondary outcome [1] 0 0
Area Under the Concentration-Time Curve (AUC) of RO7121661
Timepoint [1] 0 0
For Q2W (1 cycle is 14 days) and Q3W (1 cycle is 21 days), as indicated: Days 1-5, 8, 12 (plus Days 15 and 18 for Q3W) of Cycles 1 and 5; Days 1, 2, 5 of Cycle 2; Day 1 of Cycles 3-4 and Cycle 6 onwards through study completion (up to 27 months)
Secondary outcome [2] 0 0
Maximum Concentration (Cmax) of RO7121661
Timepoint [2] 0 0
For Q2W (1 cycle is 14 days) and Q3W (1 cycle is 21 days), as indicated: Days 1-5, 8, 12 (plus Days 15 and 18 for Q3W) of Cycles 1 and 5; Days 1, 2, 5 of Cycle 2; Day 1 of Cycles 3-4 and Cycle 6 onwards through study completion (up to 27 months)
Secondary outcome [3] 0 0
Total Clearance (CL) of RO7121661
Timepoint [3] 0 0
For Q2W (1 cycle is 14 days) and Q3W (1 cycle is 21 days), as indicated: Days 1-5, 8, 12 (plus Days 15 and 18 for Q3W) of Cycles 1 and 5; Days 1, 2, 5 of Cycle 2; Day 1 of Cycles 3-4 and Cycle 6 onwards through study completion (up to 27 months)
Secondary outcome [4] 0 0
Volume of Distribution at Steady State of RO7121661
Timepoint [4] 0 0
For Q2W (1 cycle is 14 days) and Q3W (1 cycle is 21 days), as indicated: Days 1-5, 8, 12 (plus Days 15 and 18 for Q3W) of Cycles 1 and 5; Days 1, 2, 5 of Cycle 2; Day 1 of Cycles 3-4 and Cycle 6 onwards through study completion (up to 27 months)
Secondary outcome [5] 0 0
Terminal Half-Life (t1/2) of RO7121661
Timepoint [5] 0 0
For Q2W (1 cycle is 14 days) and Q3W (1 cycle is 21 days), as indicated: Days 1-5, 8, 12 (plus Days 15 and 18 for Q3W) of Cycles 1 and 5; Days 1, 2, 5 of Cycle 2; Day 1 of Cycles 3-4 and Cycle 6 onwards through study completion (up to 27 months)
Secondary outcome [6] 0 0
Percentage of Participants with Anti-Drug Antibodies
Timepoint [6] 0 0
For Q2W (1 cycle is 14 days) and Q3W (1 cycle is 21 days): Day 1 of Cycles 1 to 5; Day 1 of Cycle 7, and every 3 (for Q3W) or every 6 (for Q2W) cycles afterwards through study completion (up to 27 months)
Secondary outcome [7] 0 0
Receptor Occupancy of RO7121661, Assessed via an Ex-Vivo Assay
Timepoint [7] 0 0
For Parts A1 (Q2W) and A2 (Q3W), as shown: Days 1, 8 (plus Day 15 for Q3W) of Cycles 1, 5; Day 1 of Cycles 2, 3; and Day 1 of Cycles 9, 22, 35, 48 (for Q2W) or Cycles 7, 15, 23, 31 (for Q3W) through study completion (up to 27 months)
Secondary outcome [8] 0 0
Examine Profile and Status of T-cell Proliferation/Activation in Tumor Biopsies and Peripheral Blood - For Q2W: 1 cycle is 14 days; for Q3W: 1 cycle is 21 days
Timepoint [8] 0 0
For Parts B1-3 (Q2W/Q3W): At screening; Days 1, 2, 8 (and Day 15 for Q3W) of Cycles 1, 5; Day 1 (and Day 5 for Q3W) of Cycle 2; Day 1 Cycle 3 and Cycles 9, 22, 35, 48 (for Q2W) or Cycles 7, 15, 23, 31 (for Q3W) through study completion (up to 27 months)

Eligibility
Key inclusion criteria
General

- For Part A only: Patients with advanced and/or metastatic solid tumors who have
progressed on a cancer therapy, for whom no effective standard therapy exists, or who
decline treatment with approved therapies

- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 and a life expectancy
of greater than or equal to (=)12 weeks

- Adequate cardiovascular, hematological, liver, and renal function

- Adverse events from any prior radiotherapy, chemotherapy, or surgical procedure must
have resolved to Grade =1, except alopecia (any grade), vitiligo, endocrinopathy
managed with replacement therapy, and Grade 2 peripheral neuropathy

- Additional adequate laboratory parameters obtained within 14 days prior to the first
study treatment (Cycle [C] 1, Day [D] 1)

- Participants on therapeutic anticoagulation should be on a stable anticoagulant
regimen

- Negative HIV and hepatitis B surface antigen (HBsAg) test at screening

- Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total
HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening

- Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody
test followed by a negative HCV RNA test at screening

- Diagnosis of locally advanced and/or metastatic solid tumors with radiologically
measurable disease according to RECIST v1.1

- Female participants who are not pregnant, not breastfeeding, and at least one of the
following conditions applies: Not a woman of childbearing potential (WOCBP); or a
WOCBP who: 1) Agrees to remain abstinent or use contraceptive methods that result in a
failure rate of <1% per year during the treatment period and for at least 4 months
after the last dose of RO7121661; and 2) Has a negative pregnancy test (blood) within
the 7 days prior to the first study RO7121661 administration

- Male participants: During the treatment period and for at least 4 months after the
last dose of RO7121661, agreement to: 1) Remain abstinent or use contraceptive
measures such as a condom plus an additional contraceptive method that together result
in a failure rate of <1% per year, with partners who are women of childbearing
potential and/or with pregnant female partners; and 2) Refrain from donating sperm for
4 months

Specific Inclusion Criteria for Biopsies:

- Participants who are enrolled on the parts of the study where fresh biopsies are
requested must have at least one non-target tumor lesion accessible to biopsy per clinical
judgment of the treating physician and consent to undergo mandatory fresh baseline and
on-treatment biopsy. A lesion with evidence of progression by imaging (or measurement for
cutaneous lesions) is preferred if it can be assessed accurately. Bone lesion biopsies,
bronchoscopy/trans-bronchial biopsies, and cytology fine needle aspirates are not
acceptable (applicable for Expansion in Parts B1 and B2 [CPI Experienced Patients], Part B3
[Untreated CIT-Naïve NSCLC], and Part B4 [CPI-Naïve SCLC])

Specific Inclusion Criteria for Part B1 and Part B2 Expansion Cohorts (Checkpoint Inhibitor
[CPI] Experienced Patients):

- Participants with advanced and/or metastatic malignancies who have progressed on an
anti-programmed death-ligand 1 (PD-L1)/anti-programmed death-1 (PD-1) agent

- The non-small cell lung cancer (NSCLC) participants must have experienced initial
clinical benefit from CPI therapy for at least 4 months in which there was at least
one interval scan prior to 4 months demonstrating no progression of disease

- Participants who are considered to be deriving benefit from treatment post
progression, as per clinical judgment, are not considered eligible. Screening tumor
assessment should confirm progression

- Prior anti-PD-L1/anti-PD-1 as monotherapy and/or as combination therapy may have been
administered as indicated for the respective indications, with the exception of
adjuvant therapy

- For Part B1 (CPI-Experienced Metastatic Melanoma): Participants with histologically
confirmed advanced metastatic melanoma previously treated with approved
anti-PD-L1/anti-PD-1 agents with or without approved anti-cytotoxic
T-lymphocyte-associated protein 4 (CTLA-4) therapy and up to one additional treatment
regimen

- For Part B2 (CPI-Experienced NSCLC): Participants with histologically confirmed
advanced NSCLC previously treated with PD-L1/PD-1 inhibitors (investigational or
approved) and platinum based chemotherapy, either sequentially or concurrently

Specific Inclusion Criteria for Expansion Part B3 in Untreated Cancer Immunotherapy
(CIT)-Naïve NSCLC Cohort:

- Histologically confirmed advanced NSCLC with PD-L1 high. Can be based on historic results
or analysis of archival or fresh biopsy.

Specific Inclusion Criteria for Expansion Part B4 in CPI-Naïve Small Cell Lung Cancer
(SCLC) Cohort:

- Histologically confirmed SCLC

- May have had prior chemotherapy, radiation therapy or declined approved therapies for
SCLC
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
General

- Known hypersensitivity to any of the components of RO7121661

- History or clinical evidence of central nervous system primary tumors or metastases
including leptomeningeal metastases, unless they have been previously treated, are
asymptomatic, and have had no requirement for steroids or enzyme-inducing
anticonvulsants in the last 14 days prior to Screening

- Participants with an active second malignancy

- Evidence of significant, uncontrolled concomitant diseases that could affect
compliance with the protocol or interpretation of results, including diabetes
mellitus, history of relevant pulmonary disorders, and known autoimmune diseases or
immune deficiency, or other disease with ongoing fibrosis

- Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed
consent

- Severe dyspnea or requiring supplemental oxygen therapy at rest

- Significant cardiovascular/cerebrovascular vascular disease within 6 months prior to
D1 of study drug administration

- Known active or uncontrolled bacterial, viral, fungal, mycobacterial, parasitic, or
other infection or any major episode of infection requiring treatment with IV
antibiotics or hospitalization within 4 weeks prior to the start of drug
administration

- Vaccination with live vaccines within 28 days prior to the start of treatment

- Known clinically significant liver disease

- Major surgical procedure or significant traumatic injury within 28 days prior to C1D1,
or anticipation of the need for major surgery during the course of the study

- 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 participant at high risk from treatment
complications

- Dementia or altered mental status that would prohibit informed consent

- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures

- Active or history of autoimmune disease or immune deficiency

- For Part A, Part B1 (CPI experienced melanoma patients), and Part B2 (CPI and platinum
experienced NSCLC patients): prior treatment with CPIs, immunomodulatory monoclonal
antibodies (mAbs), and/or mAb-derived therapies is allowed (approved or
investigational), with the following exceptions: <4 weeks have elapsed between the
last dose of prior anti-PD-1 and the proposed C1D1; <5 half-lives or 28 days
(whichever is shorter) have elapsed from prior treatment with specific
immunomodulators, TLR agonists, inhibitors of IDO/TDO, or agonists; Prior treatment
with adoptive cell therapies, such as CAR-T therapies is not permitted

- For Part B2 (PD-1/PD-L1 and chemotherapy experienced NSCLC patients): prior treatment
with immunomodulatory agents for cancer therapy, other than anti-PD-1 or anti-PD-L1
agents, is prohibited

- Prior treatment with a TIM-3 inhibitor or LAG-3 inhibitor is prohibited

- Concurrent therapy with any other investigational drug <28 days or 5 half-lives of the
drug, whichever is shorter, prior to the first RO7121661 administration on C1D1, is
prohibited

- Immuno-modulating agents: Last dose with any of the following agents, for example,
etanercept, infliximab, tacrolimus, cyclosporine, mycophenolic acid, alefacept, or
efalizumab <28 days prior to C1D1 and regular immunosuppressive therapy are prohibited

- Chronic use of steroids (excluding topical and inhaled) and concurrent high doses of
systemic corticosteroids will not be allowed

- Radiotherapy within the last 4 weeks before start of study drug treatment is not
allowed, with the exception of limited palliative radiotherapy

- Eligibility of participants who require blood transfusion before and after the start
of the study treatment should be discussed by the Sponsor and Investigator

Specific Exclusion Criteria for Part B1 and Part B2 Expansion Cohorts (CPI Experienced
Patients):

- Any history of an immune-related Grade 4 adverse event attributed to prior CIT

- Any history of an immune-related adverse event attributed to prior CIT that resulted
in permanent discontinuation of the prior immunotherapeutic agent and/or occurred =6
months prior to planned C1D1

- All immune-related adverse events related to prior immunomodulatory therapy must have
resolved completely to baseline. Participants treated with corticosteroids for
immune-related adverse events must demonstrate absence of related symptoms or signs
for =4 weeks following discontinuation of corticosteroids

Specific Exclusion Criteria for Part B2 Expansion NSCLC Cohort:

- NSCLC patients with the following mutations, rearrangements, translocations are not
eligible for Part B2: epidermal growth factor receptor (EGFR); anaplastic lymphoma kinase
(ALK); ROS proto-oncogene 1 (ROS1), BRAFV600E, neurotrophic receptor tyrosine kinase (NTRK)

Specific Exclusion Criteria for Part B3 Expansion Untreated CIT-Naïve NSCLC Cohort:

- Prior therapy for metastatic disease is not permitted

- Adjuvant anti-PD-1 or anti-PD-L1 therapy is not allowed. Adjuvant chemotherapy is
permitted as long as treatment was administered >6 months prior

Specific Exclusion Criteria for Part B4 Expansion CPI-Naïve SCLC Cohort:

- Prior therapy with any immune CPIs (such as anti-PD-L1/PD-1, CTLA-4), is not permitted

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Massachusetts
Country [2] 0 0
United States of America
State/province [2] 0 0
New York
Country [3] 0 0
United States of America
State/province [3] 0 0
Texas
Country [4] 0 0
Denmark
State/province [4] 0 0
Herlev
Country [5] 0 0
Denmark
State/province [5] 0 0
København Ø
Country [6] 0 0
France
State/province [6] 0 0
Bordeaux
Country [7] 0 0
France
State/province [7] 0 0
Lyon
Country [8] 0 0
France
State/province [8] 0 0
Marseille
Country [9] 0 0
Korea, Republic of
State/province [9] 0 0
Seoul
Country [10] 0 0
Netherlands
State/province [10] 0 0
Amsterdam
Country [11] 0 0
Netherlands
State/province [11] 0 0
Rotterdam
Country [12] 0 0
New Zealand
State/province [12] 0 0
Auckland
Country [13] 0 0
Spain
State/province [13] 0 0
Navarra
Country [14] 0 0
Spain
State/province [14] 0 0
Barcelona
Country [15] 0 0
Spain
State/province [15] 0 0
Madrid
Country [16] 0 0
Spain
State/province [16] 0 0
Valencia

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Hoffmann-La Roche
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This is a first-in-human, open-label, multicenter, Phase I multiple-ascending dose (MAD)
study of single agent RO7121661, an anti PD-1 (programmed death-1) and TIM-3 (T-cell
immunoglobulin and mucin domain 3) bispecific antibody, for participants with advanced and/or
metastatic solid tumors. The study consists of 2 parts: Dose Escalation (Parts A1 and A2) and
Expansion (Parts B1, B2, B3, and B4). The Dose Escalation part will be conducted first to
determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) based
on safety, tolerability, pharmacokinetic, and/or the pharmacodynamic profile of escalating
doses of RO7121661. The Expansion part will enroll tumor-specific cohorts to evaluate
anti-tumor activity of the MTD and/or RDE of RO7121661 from Part A (Q2W and if available,
Q3W) and to confirm safety and tolerability in participants with selected tumor types.
Trial website
https://clinicaltrials.gov/show/NCT03708328
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Reference Study ID Number: NP40435 www.roche.com/about_roche/roche_worldwide.htm
Address 0 0
Country 0 0
Phone 0 0
888-662-6728 (U.S. Only)
Fax 0 0
Email 0 0
global-roche-genentech-trials@gene.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03708328