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A Study of RO5509554 as Monotherapy and in Combination With Paclitaxel in Participants With Advanced Solid Tumors

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01494688
First received: December 2, 2011
Last updated: November 1, 2016
Last verified: November 2016
  Purpose
This open-label, multicenter, dose-escalation study will assess the safety, tolerability, pharmacokinetics and pharmacodynamics of RO5509554 in participants with advanced solid tumors which are not amenable to standard treatment. In Part I (Dose Escalation), multiple ascending doses of RO5509554 will be administered as monotherapy in participants with solid tumors. Participants with locally advanced and/or metastatic ovarian (including fallopian tube) and breast carcinoma will receive multiple ascending doses of RO5509554 in combination with paclitaxel. In Part II (Expansion Cohort), RO5509554 will be administered as monotherapy to participants with locally advanced and/or metastatic Pigmented Villonodular Synovitis (PVNS)/Tenosynovial Giant Cell Tumor (TGCT), soft tissue sarcoma or malignant mesothelioma, ovarian (including fallopian tube), endometrial or breast cancer and pancreatic cancer. Participants with Human Epidermal Growth Factor Receptor 2 (HER2)/neu negative breast cancer will receive RO5509554 in combination with paclitaxel. Anticipated time on study treatment is until disease progression, unacceptable toxicity, death or participant refusal, whichever occurs first.

Condition Intervention Phase
Advanced Solid Tumors
Drug: Paclitaxel
Drug: RO5509554
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Open-Label, Multicenter, Dose Escalation Phase Ia/Ib Study With Expansion Phase to Evaluate Safety, Pharmacokinetics and Activity of RO5509554, Administered as an Intravenous Infusion as Monotherapy and in Combination With Paclitaxel in Patients With Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Percentage of Participants With Adverse Events [ Time Frame: Baseline up to 28 days after last dose (approximately 48 months) ] [ Designated as safety issue: No ]
  • Part 1: Maximum Tolerated Dose (MTD)/Optimal Biological Dose (OBD) of RO5509554 as a Single Agent and in Combination With Paclitaxel [ Time Frame: Cycle 1 Day 1 (cycle length = 14 or 21 days) up to 28 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Part 2: Change in Colony Stimulating Factor-1 (CSF-1) Serum Level For Every 2 Weeks (Q2W) Schedule [ Time Frame: Pre-dose (0 hour [h]), 2, 5, 24, 72 or 96, 168, 216 and 264 h post-dose Cycles 1 & 4; 0 h & any time on Day 8 Cycle 2; 0 h Cycle 3; 0 h Cycle 5 & any time during 28 days follow-up; 0 h Cycle 6 onward up to 48 months [Each cycle=14 days] ] [ Designated as safety issue: No ]
  • Part 2: Change in CSF-1 Serum Level For Every 3 Weeks (Q3W) Schedule [ Time Frame: Pre-dose (0 h), 3, 24, 72, 168, 264, 312, 432 & 480 h post-dose Cycles 1 & 4; 0 h Cycles 2 & 3; 0 h Cycle 5 & any time during 28 days follow-up; 0 h Cycle 6 onward up to 48 months [Each cycle=21 days] ] [ Designated as safety issue: No ]
  • Part 2: Change in CSF-1 Serum Level For Initial Q2W Followed by Monthly Maintenance Schedule [ Time Frame: Pre-dose (0 h), 2, 5, 24, 72 or 96, 168, 216 & 264 h post-dose Cycle 1; 0 h & any time on Day 8 Cycle 2; 0 h & 5, 24, 72 or 96, 168, 264, 336, 432, 504 & 576 h post-dose Cycle 3; 0 h Cycle 4 onward up to 48 months [Each cycle=14 or 30 days] ] [ Designated as safety issue: No ]
  • Change in Circulating Monocytes Subset in Whole Blood For Q2W Schedule [ Time Frame: 0,2,5,24,72 or 96,168,216 & 264 h post-dose Cycle 1; 0 h Day 1, any time Day 8 Cycle 2; 0 h Cycles 3 & 5; 0,5,72 or 96,168,216 & 264 h post-dose Cycle 4 & any time during 28 days follow-up; 0 h Cycle 6 onward up to 48 months [Each cycle=14 days] ] [ Designated as safety issue: No ]
  • Change in Circulating Monocytes Subset in Whole Blood For Q3W Schedule [ Time Frame: 0, 3, 24, 72, 168, 264, 312, 432 & 480 h post-dose Cycle 1; 0 h Cycles 2 & 3; 0, 3, 72, 168, 264, 312, 432 & 480 h post-dose Cycle 4; 0 h Cycle 5 & any time during 28 days follow-up; 0 h Cycle 6 onward up to 48 months [Each cycle=21 days] ] [ Designated as safety issue: No ]
  • Change in Circulating Monocytes Subset in Whole Blood For Initial Q2W Followed by Monthly Maintenance Schedule [ Time Frame: Pre-dose (0 h), 2, 5, 24, 72 or 96, 168, 216 & 264 h post-dose Cycle 1; 0 h & any time on Day 8 Cycle 2; 0h & 5, 24, 72 or 96, 168, 264, 336, 432, 504 & 576 h post-dose Cycle 3; 0 h Cycle 4 onward up to 48 months [Each cycle=14 or 30 days] ] [ Designated as safety issue: No ]
  • Pharmacokinetics of RO5509554: Area Under the Plasma concentration-Time Curve (AUC) for Q2W Schedule [ Time Frame: Pre-dose(0 h),end of infusion(EOI)(over 1.5 h)& 3,4,5,6,24,72 or 96,168,216&264 h post-dose Cycle 1;0 h & EOI Cycles 2,3&5; 0 h,EOI &2,3,4,5,6,24,72 or 96,168,216&264 h post-dose at Cycle 4;0 h,EOI Cycle 6 onward up to 48 months [Each cycle=14 days] ] [ Designated as safety issue: No ]
  • Pharmacokinetics of RO5509554: AUC for Q3W Schedule [ Time Frame: Pre-dose (0 h), EOI (over 1.5 h) and 3, 24, 72, 168, 264, 312, 432 and 480 h post-dose Cycles 1 and 4; pre-dose (0 h) and EOI Cycles 2, 3 and 5; pre-dose (0 h), EOI Cycle 6 onwards up to 48 months [Each cycle=21 days] ] [ Designated as safety issue: No ]
  • Pharmacokinetics of RO5509554: AUC for Initial Q2W Followed by Monthly Maintenance Schedule [ Time Frame: Pre-dose(0 h),EOI(over 1.5 h), 3, 5, 24, 72 or 96, 168, 216, 264 h post-dose Cycle 1; 0 h & EOI Cycle 2; 0 h, EOI & 3, 5, 24, 72 or 96, 168, 264, 336, 432, 504, 576 h post-dose Cycle 3; 0 h & EOI Cycle 4 onward up to 48 months [Each cycle=14 or 30 days] ] [ Designated as safety issue: No ]
  • Pharmacokinetics of RO5509554: Maximum Observed Plasma concentration (Cmax) for Q2W Schedule [ Time Frame: Pre-dose(0 h), EOI (over 1.5 h) & 3,4,5,6,24,72 or 96,168,216&264 h post-dose Cycle 1;0 h & EOI Cycles 2,3&5; 0 h,EOI &2,3,4,5,6,24,72 or 96,168,216&264 h post-dose at Cycle 4;0 h,EOI Cycle 6 onward up to 48 months [Each cycle=14 days] ] [ Designated as safety issue: No ]
  • Pharmacokinetics of RO5509554: Cmax for Q3W Schedule [ Time Frame: Pre-dose (0 h), EOI (over 1.5 h) and 3, 24, 72, 168, 264, 312, 432 and 480 h post-dose Cycles 1 and 4; pre-dose (0 h) and EOI Cycles 2, 3 and 5; pre-dose (0 h), EOI Cycle 6 onwards up to 48 months [Each cycle=21 days] ] [ Designated as safety issue: No ]
  • Pharmacokinetics of RO5509554: Cmax for Initial Q2W Followed by Monthly Maintenance Schedule [ Time Frame: Pre-dose(0 h),EOI(over 1.5 h), 3, 5, 24, 72 or 96, 168, 216, 264 h post-dose Cycle 1; 0 h & EOI Cycle 2; 0 h, EOI & 3, 5, 24, 72 or 96, 168, 264, 336, 432, 504, 576 h post-dose Cycle 3; 0 h & EOI Cycle 4 onward up to 48 months [Each cycle=14 or 30 days] ] [ Designated as safety issue: No ]
  • Pharmacokinetics of RO5509554: Half-life (t1/2) for Q2W Schedule [ Time Frame: Pre-dose(0 h), EOI (over 1.5 h) & 3,4,5,6,24,72 or 96,168,216&264 h post-dose Cycle 1;0 h & EOI Cycles 2,3&5; 0 h,EOI &2,3,4,5,6,24,72 or 96,168,216&264 h post-dose at Cycle 4;0 h,EOI Cycle 6 onward up to 48 months [Each cycle=14 days] ] [ Designated as safety issue: No ]
  • Pharmacokinetics of RO5509554: t1/2 for Q3W Schedule [ Time Frame: Pre-dose (0 h), EOI (over 1.5 h) and 3, 24, 72, 168, 264, 312, 432 and 480 h post-dose Cycles 1 and 4; pre-dose (0 h) and EOI Cycles 2, 3 and 5; pre-dose (0 h), EOI Cycle 6 onwards up to 48 months [Each cycle=21 days] ] [ Designated as safety issue: No ]
  • Pharmacokinetics of RO5509554: t1/2 Initial Q2W Followed by Monthly Maintenance Schedule [ Time Frame: Pre-dose(0 h),EOI(over 1.5 h), 3, 5, 24, 72 or 96, 168, 216, 264 h post-dose Cycle 1; 0 h & EOI Cycle 2; 0 h, EOI & 3, 5, 24, 72 or 96, 168, 264, 336, 432, 504, 576 h post-dose Cycle 3; 0 h & EOI Cycle 4 onward up to 48 months [Each cycle=14 or 30 days] ] [ Designated as safety issue: No ]
  • Pharmacokinetics of RO5509554: Systemic Clearance (CL) for Q2W Schedule [ Time Frame: Pre-dose(0 h), EOI (over 1.5 h) & 3,4,5,6,24,72 or 96,168,216&264 h post-dose Cycle 1;0 h & EOI Cycles 2,3&5; 0 h,EOI &2,3,4,5,6,24,72 or 96,168,216&264 h post-dose at Cycle 4;0 h,EOI Cycle 6 onward up to 48 months [Each cycle=14 days] ] [ Designated as safety issue: No ]
  • Pharmacokinetics of RO5509554: CL for Q3W Schedule [ Time Frame: Pre-dose (0 h), EOI (over 1.5 h) and 3, 24, 72, 168, 264, 312, 432 and 480 h post-dose Cycles 1 and 4; pre-dose (0 h) and EOI Cycles 2, 3 and 5; pre-dose (0 h), EOI Cycle 6 onwards up to 48 months [Each cycle=21 days] ] [ Designated as safety issue: No ]
  • Pharmacokinetics of RO5509554: CL for Initial Q2W Followed by Monthly Maintenance Schedule [ Time Frame: Pre-dose(0 h),EOI(over 1.5 h), 3, 5, 24, 72 or 96, 168, 216, 264 h post-dose Cycle 1; 0 h & EOI Cycle 2; 0 h, EOI & 3, 5, 24, 72 or 96, 168, 264, 336, 432, 504, 576 h post-dose Cycle 3; 0 h & EOI Cycle 4 onward up to 48 months [Each cycle=14 or 30 days] ] [ Designated as safety issue: No ]
  • Change in Pharmacodynamic Markers: Dermal Macrophages Expressing CD68/CD163 and Colony Stimulating Factor-1 Receptor (CSF-1R) in Paired Skin Biopsies [ Time Frame: Baseline, Day 1 Cycle 2 pre-dose (0 h), Day 8 Cycle 2 [Each Cycle = 14 or 21 days] ] [ Designated as safety issue: No ]
  • Change in Pharmacodynamic Markers: Dermal Macrophages Expressing CD68/CD163 and CSF-1R in Paired Tumor Biopsies [ Time Frame: Day -21 to -14, pre-dose (0 h) Day 1 Cycle 3 [Each Cycle = 14 or 21 days] ] [ Designated as safety issue: No ]
  • Change in Pharmacodynamic Markers: Tumor associated Macrophages (TAM) expressing Cells in Surrogate/Tumor Tissue (in Paired Tumor Biopsies) [ Time Frame: Day -21 to -14, pre-dose (0 h) Day 1 Cycle 3 [Each Cycle = 14 or 21 days] ] [ Designated as safety issue: No ]
  • Standard Uptake Value of 18F Fluoro-Deoxy-Glucose (FDG), as Assessed Using Positron Emission Tomography (PET) Imaging [ Time Frame: Baseline up to Cycle 3 Days 1 or 7 (Cycle length = 14 or 21 days) ] [ Designated as safety issue: No ]
  • Part 1: Recommended Phase II Dose (RP2D) of RO5509554 [ Time Frame: Cycle 1 Day 1 (cycle length = 14 or 21 days) up to 28 days ] [ Designated as safety issue: No ]
  • Percentage of Participants With Objective Response (OR) Assessed According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: From screening to disease progression, death, withdrawal, or end of study; assessed at screening (within 3 weeks before first dose of study drug) then Day 1 of every third cycle (Each Cycle=14 or 21 days) until end of treatment (approximately 48 months) ] [ Designated as safety issue: No ]
  • Percentage of Participants With Clinical Benefit Assessed According to RECIST Version 1.1 [ Time Frame: From screening to disease progression, death, withdrawal, or end of study; assessed at screening (within 3 weeks before first dose of study drug) then Day 1 of every third cycle (Each Cycle=14 or 21 days) until end of treatment (approximately 48 months) ] [ Designated as safety issue: No ]
  • Progression Free Survival (PFS) Assessed According to RECIST Version 1.1 [ Time Frame: From screening to disease progression, death, withdrawal, or end of study; assessed at screening (within 3 weeks before first dose of study drug) then Day 1 of every third cycle (Each Cycle=14 or 21 days) until end of treatment (approximately 48 months) ] [ Designated as safety issue: No ]
  • Duration of Response Assessed According to RECIST Version 1.1 [ Time Frame: From screening to disease progression, death, withdrawal, or end of study; assessed at screening (within 3 weeks before first dose of study drug) then Day 1 of every third cycle (Each Cycle=14 or 21 days)) until end of treatment (approximately 48 months) ] [ Designated as safety issue: No ]

Enrollment: 217
Study Start Date: December 2011
Estimated Study Completion Date: April 2018
Estimated Primary Completion Date: April 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part 1 - Dose Escalation: RO5509554
Participants will receive a single, low dose of 100 milligrams (mg) RO5509554 in 7-day PK run-in period (Cycle 0), followed by dose escalation from Day 1 of Cycle 1. RO5509554 will be escalated as monotherapy in approximately 6 cohorts with dose increments between cohorts of up to 100 percent (%). The doses will be escalated further until MTD/OBD as single agent is reached.
Drug: RO5509554
RO5509554 will be administered Q2W, Q3W or initial biweekly followed by monthly maintenance as intravenous (IV) infusion until disease progression, unacceptable toxicity, death or participant refusal, whichever occurs first.
Other Name: RG7155
Experimental: Part 1 - Dose Escalation: RO5509554 + Paclitaxel
RO5509554 will be administered in combination with a fixed dose of weekly (QW) paclitaxel (80 milligrams per square meter [mg/m^2]). The starting dose for RO5509554 in combination with paclitaxel will be 2 dose levels below to that of the highest dose of monotherapy RO5509554. Escalation of RO5509554 in combination with QW paclitaxel will start in a standard 3 + 3 design until MTD/OBD as combination dose is reached. If the initial combination is not tolerated, further cohorts will be dosed with the same dose of paclitaxel and lower dose of RO5509554. If insufficient safety, pharmacokinetic or pharmacodynamic data have been collected at the MTD/OBD, up to an additional 4 participants may be enrolled at that dose level.
Drug: Paclitaxel
Paclitaxel, at a dose of 80 mg/m^2 will be administered QW for up to 12 weeks.
Drug: RO5509554
RO5509554 will be administered Q2W, Q3W or initial biweekly followed by monthly maintenance as intravenous (IV) infusion until disease progression, unacceptable toxicity, death or participant refusal, whichever occurs first.
Other Name: RG7155
Experimental: Part 2 - Expansion Cohort: RO5509554
Participants will receive RO5509554 1000 mg Q2W, Q3W or initial biweekly followed by monthly maintenance.
Drug: RO5509554
RO5509554 will be administered Q2W, Q3W or initial biweekly followed by monthly maintenance as intravenous (IV) infusion until disease progression, unacceptable toxicity, death or participant refusal, whichever occurs first.
Other Name: RG7155
Experimental: Part 2 - Expansion Cohort: RO5509554 + Paclitaxel
Participants will receive RO5509554 1000 mg Q2W in combination with a fixed dose of QW paclitaxel (80 mg/m^2).
Drug: Paclitaxel
Paclitaxel, at a dose of 80 mg/m^2 will be administered QW for up to 12 weeks.
Drug: RO5509554
RO5509554 will be administered Q2W, Q3W or initial biweekly followed by monthly maintenance as intravenous (IV) infusion until disease progression, unacceptable toxicity, death or participant refusal, whichever occurs first.
Other Name: RG7155

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed advanced and/or metastatic solid tumors which are not amenable to standard therapy, with exceptions as defined in exclusion criteria
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  • Measurable disease according to RECIST criteria version 1.1
  • Adequate bone marrow, cardiac, liver and renal function

Exclusion Criteria:

  • Participants with histologically proven Hepatocellular Carcinoma (HC), Non Small Cell Lung Cancer (NSCLC), Small Cell Lung Cancer (SCLC), gastric cancer, malignant melanoma, nonmetastatic and locally controlled PVNS/TGCT
  • Participants with known auto-immune disease
  • Known or suspected central nervous system (CNS) metastases including leptomeningeal metastasis; participants with radiologically stable, asymptomatic previously irradiated lesion are eligible provided participant is greater than or equal to (>/=) 4 weeks beyond completing cranial irradiation and >/= 3 weeks of corticosteroid therapy
  • Significant, uncontrolled concomitant diseases, including significant cardiovascular or pulmonary disease
  • Prior chemotherapy, radiotherapy (other than short cycle of palliative radiotherapy for bone pain), any investigational agent or immunotherapy within 28 days of first receipt of study drug
  • Prior corticosteroids as anti-cancer therapy within minimum of 14 days of first receipt of study drug
  • Poorly controlled type 1 or type 2 diabetes mellitus
  • Prior toxicities from chemotherapy or radiotherapy which have not regressed to Grade less than or equal to (</=) 1 severity National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 or later versions
  • Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infection
  • Pulmonary embolism or any other thrombo-embolic event within 6 months prior to study entry
  • History of hematological malignancy within the last 5 years prior to study entry
  • Participant requires high dose corticosteroid treatment ( i.e. greater than (>) 20 mg dexamethasone a day or equivalent for > 7 consecutive days)
  • Any surgical procedure, including the required baseline tumor biopsy, within less than 14 days of first receipt of study drug. Major surgery within 28 days of first receipt of study drug
  • Pregnant or lactating women
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01494688

Locations
United States, New York
New York, New York, United States, 10065
United States, Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
France
Bordeaux, France, 33076
Lyon, France, 69373
Paris, France, 75231
Saint Herblain, France, 44805
Toulouse, France, 31059
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01494688     History of Changes
Other Study ID Numbers: BP27772  2011-003394-28 
Study First Received: December 2, 2011
Last Updated: November 1, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Paclitaxel
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on December 05, 2016