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A Study of RO6958688 in Participants With Locally Advanced and/or Metastatic Carcinoembryonic Antigen Positive Solid Tumors

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ClinicalTrials.gov Identifier: NCT02324257
Recruitment Status : Active, not recruiting
First Posted : December 24, 2014
Last Update Posted : August 6, 2018
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
Study BP29541 is a first-in-human, open-label, multi-center, dose-escalation Phase I clinical study of single-agent RO6958688 in participants with locally advanced and/or metastatic carcinoembryonic antigen (CEA) positive solid tumors who have progressed on standard treatment, are intolerant to standard of care (SOC), and/or are non-amenable to SOC. The study will be conducted in two parts. Part I of the study will investigate the safety and pharmacokinetics of a single dose of RO6958688 in single participant cohorts with dosing starting from a minimal anticipated biological effect level dose of 0.05 milligrams (mg) and up to a maximum dose of 2.5 mg. Part II will establish the appropriate therapeutic dose based on safety, pharmacokinetics, and the maximum tolerated dose (MTD) of RO6958688 for the once per week (QW) regimen, every three weeks (Q3W) regimen, and for the step up dosing regimen. The overall target sample size is approximately 185 evaluable participants.

Condition or disease Intervention/treatment Phase
Solid Tumors Drug: RO6958688 Drug: Obinutuzumab Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 185 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Multicenter, Dose-Escalation Phase I Study to Evaluate the Safety, Pharmacokinetics, and Therapeutic Activity of RO6958688, A Novel T-cell Bispecific Antibody That Targets the Human Carcinoembryonic Antigen (CEA) on Tumor Cells and CD3 on T Cells, Administered Intravenously in Patients With Locally Advanced and/or Metastatic CEA(+) Solid Tumors
Actual Study Start Date : December 30, 2014
Estimated Primary Completion Date : August 31, 2019
Estimated Study Completion Date : August 31, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Part I: RO6958688
Participants will receive single dose of RO6958688 starting from a dose of 0.05, 0.15, 0.45, 1.3, and 2.5 mg in Part I of the study.
Drug: RO6958688
RO6958688 is given as an intravenous (IV) infusion as a single administration in Part I and as QW or Q3W administration (cycle = 7 days in the QW regimen and cycle = 21 days in the Q3W regimen) in Part II of the study.

Experimental: Part II: RO6958688 With/Without Obinutuzumab Pretreatment
Participants will receive MTD (or lower dose) of RO6958688 with or without obinutuzumab pretreatment in Part II of the study and different dosing schedules will be assessed.
Drug: RO6958688
RO6958688 is given as an intravenous (IV) infusion as a single administration in Part I and as QW or Q3W administration (cycle = 7 days in the QW regimen and cycle = 21 days in the Q3W regimen) in Part II of the study.

Drug: Obinutuzumab
Obinutuzumab is given as an IV infusion at a dose level of 2000 mg on Day -13 or 1000 mg on Days -13 and -12 prior to the treatment start with RO6958688 on Cycle 1 Day 1.




Primary Outcome Measures :
  1. Percentage of Participants with Adverse Events (AEs) or Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 40 months ]
  2. Percentage of Participants with Dose-Limiting Toxicities (DLTs) [ Time Frame: Day 1 up to Day 21 ]
  3. Percentage of Participants With Anti-Drug Antibodies (ADAs) Against RO6958688 [ Time Frame: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 40 months (detailed timeframe is provided in outcome description section) ]
    Part I: Pre-dose (Hour 0) on Day 1 of Cycles 1, 2-3; 120 hours after end of infusion (EOI) in Cycle 1. Part II QW: pre-dose (Hour 0) on Day 1 of Cycles 1, 2, 3, 4. Part II Q3W: pre-dose (Hour 0) on Day 1 of Cycles 1, 2, 3, 4; 120 hours and 336 hours after EOI in Cycle 1, and 120 hours after EOI in Cycles 2, 3, 4. For Part I and II (QW and Q3W): pre-dose (Hour 0) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I) up to treatment discontinuation (approximately 40 months), 28 days after last dose (approximately 40 months) (Cycle = 7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II [QW and Q3W])

  4. MTD of RO6958688 With/Without Obinutuzumab Pretreatment [ Time Frame: Day 1 up to Day 21 ]
  5. Late Cycle MTD of RO6958688 Without Obinutuzumab Pretreatment for the Step up Dosing Regimen [ Time Frame: Day 1 up to Day 7 of each cycle as long as the dose is escalate weekly in Part II QW (upto approximately 40 months; Cycle = 7 days) ]
    Late cycle MTD is defined as the highest dose with less than or equal to DLT having been observed for 6 evaluable participants. If more than 6 participants are evaluable for DLT, late cycle MTD is the highest dose where less than (<) 33% of participants have DLT.

  6. Maximum Serum Concentration (Cmax) for RO6958688 [ Time Frame: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 40 months (detailed timeframe is provided in outcome description section) ]
    Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 40 months), 28 days after last dose (approximately 40 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II [QW and Q3W])

  7. Area Under the Concentration-Time Curve (AUC) for RO6958688 [ Time Frame: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 40 months (detailed timeframe is provided in outcome description section) ]
    Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 40 months), 28 days after last dose (approximately 40 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II [QW and Q3W])

  8. Half-Life (t1/2) of RO6958688 [ Time Frame: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 40 months (detailed timeframe is provided in outcome description section) ]
    Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 40 months), 28 days after last dose (approximately 40 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II [QW and Q3W])

  9. Clearance (CL) of RO6958688 [ Time Frame: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 40 months (detailed timeframe is provided in outcome description section) ]
    Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 40 months), 28 days after last dose (approximately 40 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II [QW and Q3W])

  10. Volume of Distribution at Steady State (Vss) of RO6958688 [ Time Frame: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 40 months (detailed timeframe is provided in outcome description section) ]
    Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 40 months), 28 days after last dose (approximately 40 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II [QW and Q3W])

  11. Minimum Drug Concentration (Cmin) for RO6958688 [ Time Frame: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 40 months (detailed timeframe is provided in outcome description section) ]
    Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 40 months), 28 days after last dose (approximately 40 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II [QW and Q3W])

  12. Cmax for Obinutuzumab [ Time Frame: Screening (pre-obinutuzumab dose [Hour 0] and EOI on Day -13 or Days -13 and -12), pre-RO6958688 dose [Hour 0] on Day 1 of Cycles 1, 2, 4, 8, and 12 in Part II QW (Cycle = 7 days) ]
  13. Cmin for Obinutuzumab [ Time Frame: Screening (pre-obinutuzumab dose [Hour 0] and EOI on Day -13 or Days -13 and -12), pre-RO6958688 dose [Hour 0] on Day 1 of Cycles 1, 2, 4, 8, and 12 in Part II QW (Cycle = 7 days) ]

Secondary Outcome Measures :
  1. Percentage of Participants With an Objective Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v)1.1 [ Time Frame: Baseline up to 40 months (detailed timeframe is provided in outcome description section) ]
    Baseline up to 40 months (assessed at Screening, at 12 weeks [in Part I], at 8 weeks [in Part II QW and Q3W] after Cycle 1 Day 1, every 8 weeks for the first 12 months, thereafter every 12 weeks until disease progression or death whichever occurs first, up to 40 months) (Cycle = 7 days for Part I and II QW, and 21 days for Part II Q3W)

  2. Duration of Response According to RECIST v1.1 [ Time Frame: Baseline up to 40 months (detailed timeframe is provided in outcome description section) ]
    Baseline up to 40 months (assessed at Screening, at 12 weeks [in Part I], at 8 weeks [in Part II QW and Q3W] after Cycle 1 Day 1, every 8 weeks for the first 12 months, thereafter every 12 weeks until disease progression or death whichever occurs first, up to 40 months) (Cycle = 7 days for Part I and II QW, and 21 days for Part II Q3W)

  3. Percentage of Participants With Stable Disease According to RECIST v1.1 [ Time Frame: Baseline up to 40 months (detailed timeframe is provided in outcome description section) ]
    Baseline up to 40 months (assessed at Screening, at 12 weeks [in Part I], at 8 weeks [in Part II QW and Q3W] after Cycle 1 Day 1, every 8 weeks for the first 12 months, thereafter every 12 weeks until disease progression or death whichever occurs first, up to 40 months) (Cycle = 7 days for Part I and II QW, and 21 days for Part II Q3W)

  4. Percentage of Participants With Disease Control According to RECIST v1.1 [ Time Frame: Baseline up to 40 months (detailed timeframe is provided in outcome description section) ]
    Baseline up to 40 months (assessed at Screening, at 12 weeks [in Part I], at 8 weeks [in Part II QW and Q3W] after Cycle 1 Day 1, every 8 weeks for the first 12 months, thereafter every 12 weeks until disease progression or death whichever occurs first, up to 40 months) (Cycle = 7 days for Part I and II QW, and 21 days for Part II Q3W)

  5. Progression-Free Survival (PFS) According to RECIST v1.1 [ Time Frame: Baseline up to 40 months (detailed timeframe is provided in outcome description section) ]
    Baseline up to 40 months (assessed at Screening, at 12 weeks [in Part I], at 8 weeks [in Part II QW and Q3W] after Cycle 1 Day 1, every 8 weeks for the first 12 months, thereafter every 12 weeks until disease progression or death whichever occurs first, up to 40 months) (Cycle = 7 days for Part I and II QW, and 21 days for Part II Q3W)

  6. Change From Baseline in Activated Intra-Tumoral Cells [ Time Frame: Baseline, Day 1 of Cycles 2, 3, 4, or 7 in Part II QW and Q3W (Cycle = 7 days for Part II QW and 21 days for Part II Q3W) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • For dose escalation, locally advanced and/or metastatic gastrointestinal (GI) solid tumor in participants who have progressed on a standard therapy, are intolerant to SOC, and/or are non-amenable to SOC and other solid tumors expressing CEA. Only locally advanced and/or metastatic colorectal cancer participants should be included in the scheduled comparison expansion
  • Radiologically measurable disease according to RECIST v1.1
  • Life expectancy, in the opinion of the investigator of greater than or equal (>/=) to 12 weeks
  • Eastern Cooperative Oncology Group Performance Status of 0-1
  • All acute toxic effects of any prior radiotherapy, chemotherapy, or surgical procedure must have resolved to Grade less than or equal to 1 or returned to baseline except alopecia (any grade) and Grade 2 peripheral neuropathy
  • Adequate hematological, liver, and renal function
  • Participants must agree to be willing to use effective methods of contraception as defined in the protocol
  • Non-GI solid tumors (like non-small cell lung cancer or breast cancer) should have confirmed CEA expression in tumor tissue >/= 20% of tumor cells staining with at least moderate to high intensity of CEA expression are required (immunohistochemistry [IHC]2+ and IHC 3+). For CRC, pancreatic and gastric cancer participants, the CEA assessment will be performed retrospectively and the result is not needed to enroll the participant. For the biomarker cohort, only participants with moderate/low CEA expression (< 20% of tumor cells with IHC2+/3+ and/or >/= 20% of tumor cells with IHC1+) and very low CEA expression (< 20% of tumor cells with IHC1+) will be enrolled. CEA expression should be determined prior to enrollment, if no archival tumor tissue is available, a fresh biopsy will be collected.

Exclusion Criteria:

  • Participants with a 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 before screening
  • Participants with paraspinal, paratracheal and mediastinal pathologic lesions larger than 2 centimeters unless they are previously irradiated
  • Participants with another invasive malignancy in the last 2 years (with the exception of basal cell carcinoma and tumors deemed by the investigator to be of low likelihood for recurrence)
  • Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results or contraindicate the use of an investigational drug, including diabetes mellitus, history of relevant pulmonary disorders, and known autoimmune diseases
  • Uncontrolled hypertension (systolic blood pressure [BP] greater than [>] 150 millimeters of mercury [mmHg] and/or diastolic BP > 100 mmHg), unstable angina, congestive heart failure of any New York Heart Association classification, serious cardiac arrhythmia that requires treatment with the exceptions of atrial fibrillation and paroxysmal supraventricular tachycardia, and history of myocardial infarction within 6 months of enrollment
  • Active or uncontrolled infections
  • Known human immunodeficiency virus (HIV) or known active hepatitis B or hepatitis C infection for participants not receiving obinutuzumab pretreatment
  • Known HIV (HIV testing will be performed at screening if required by local regulations) in participants to be pretreated with obinutuzumab
  • Pregnant or breastfeeding women
  • Known hypersensitivity to any of the components of RO6958688 and/or obinutuzumab
  • Concurrent therapy with any other investigational drug
  • Expected need for regular immunosuppressive therapy
  • Regular dose of corticosteroids the 28 days prior to Day 1 of this study or anticipated need for corticosteroids that exceeds prednisone 10 mg/day or equivalent within 28 days prior to the first RO6958688 infusion. Inhaled and topical steroids are permitted
  • Radiotherapy within the last 28 days prior to the first RO6958688 infusion with the exception of limited-field palliative radiotherapy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02324257


  Show 26 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02324257     History of Changes
Other Study ID Numbers: BP29541
2014-003075-30 ( EudraCT Number )
RG7802 ( Other Identifier: Roche )
First Posted: December 24, 2014    Key Record Dates
Last Update Posted: August 6, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Obinutuzumab
Antineoplastic Agents