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

Advanced Solid Tumors Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01494688
• Other study ID #: BP27772
• Secondary ID: 2011-003394-28
• Status: Completed
• Phase: Phase 1
• First received: December 2, 2011
• Last updated: March 14, 2018
• Start date: December 20, 2011
• Est. completion date: February 7, 2018

Study information

• Verified date: March 2018
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 217
• Est. completion date: February 7, 2018
• Est. primary completion date: February 7, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Advanced Solid Tumors

Intervention

Drug:
• Paclitaxel
Paclitaxel, at a dose of 80 mg/m^2 will be administered QW for up to 12 weeks.
• 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.

Locations

Country	Name	City	State
France	Institut Bergonie; Oncologie	Bordeaux
France	Centre Leon Berard; Departement Oncologie Medicale	Lyon
France	Institut Curie; Oncologie Medicale	Paris
France	Ico Rene Gauducheau; Oncologie	Saint Herblain
France	Institut Claudius Regaud; Departement Oncologie Medicale	Toulouse
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Univ of Pennsylvania Med Ctr	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Adverse Events		Baseline up to 28 days after last dose (approximately 48 months)
Primary	Part 1: Maximum Tolerated Dose (MTD)/Optimal Biological Dose (OBD) of RO5509554 as a Single Agent and in Combination With Paclitaxel		Cycle 1 Day 1 (cycle length = 14 or 21 days) up to 28 days
Secondary	Part 2: Change in Colony Stimulating Factor-1 (CSF-1) Serum Level For Every 2 Weeks (Q2W) Schedule		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]
Secondary	Part 2: Change in CSF-1 Serum Level For Every 3 Weeks (Q3W) Schedule		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]
Secondary	Part 2: Change in CSF-1 Serum Level For Initial Q2W Followed by Monthly Maintenance Schedule		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]
Secondary	Change in Circulating Monocytes Subset in Whole Blood For Q2W Schedule		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]
Secondary	Change in Circulating Monocytes Subset in Whole Blood For Q3W Schedule		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]
Secondary	Change in Circulating Monocytes Subset in Whole Blood For Initial Q2W Followed by Monthly Maintenance Schedule		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]
Secondary	Pharmacokinetics of RO5509554: Area Under the Plasma concentration-Time Curve (AUC) for Q2W Schedule		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]
Secondary	Pharmacokinetics of RO5509554: AUC for Q3W Schedule		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]
Secondary	Pharmacokinetics of RO5509554: AUC for Initial Q2W Followed by Monthly Maintenance Schedule		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]
Secondary	Pharmacokinetics of RO5509554: Maximum Observed Plasma concentration (Cmax) for Q2W Schedule		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]
Secondary	Pharmacokinetics of RO5509554: Cmax for Q3W Schedule		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]
Secondary	Pharmacokinetics of RO5509554: Cmax for Initial Q2W Followed by Monthly Maintenance Schedule		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]
Secondary	Pharmacokinetics of RO5509554: Half-life (t1/2) for Q2W Schedule		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]
Secondary	Pharmacokinetics of RO5509554: t1/2 for Q3W Schedule		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]
Secondary	Pharmacokinetics of RO5509554: t1/2 Initial Q2W Followed by Monthly Maintenance Schedule		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]
Secondary	Pharmacokinetics of RO5509554: Systemic Clearance (CL) for Q2W Schedule		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]
Secondary	Pharmacokinetics of RO5509554: CL for Q3W Schedule		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]
Secondary	Pharmacokinetics of RO5509554: CL for Initial Q2W Followed by Monthly Maintenance Schedule		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]
Secondary	Change in Pharmacodynamic Markers: Dermal Macrophages Expressing CD68/CD163 and Colony Stimulating Factor-1 Receptor (CSF-1R) in Paired Skin Biopsies		Baseline, Day 1 Cycle 2 pre-dose (0 h), Day 8 Cycle 2 [Each Cycle = 14 or 21 days]
Secondary	Change in Pharmacodynamic Markers: Dermal Macrophages Expressing CD68/CD163 and CSF-1R in Paired Tumor Biopsies		Day -21 to -14, pre-dose (0 h) Day 1 Cycle 3 [Each Cycle = 14 or 21 days]
Secondary	Change in Pharmacodynamic Markers: Tumor associated Macrophages (TAM) expressing Cells in Surrogate/Tumor Tissue (in Paired Tumor Biopsies)		Day -21 to -14, pre-dose (0 h) Day 1 Cycle 3 [Each Cycle = 14 or 21 days]
Secondary	Standard Uptake Value of 18F Fluoro-Deoxy-Glucose (FDG), as Assessed Using Positron Emission Tomography (PET) Imaging		Baseline up to Cycle 3 Days 1 or 7 (Cycle length = 14 or 21 days)
Secondary	Part 1: Recommended Phase II Dose (RP2D) of RO5509554		Cycle 1 Day 1 (cycle length = 14 or 21 days) up to 28 days
Secondary	Percentage of Participants With Objective Response (OR) Assessed According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1		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)
Secondary	Percentage of Participants With Clinical Benefit Assessed According to RECIST Version 1.1		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)
Secondary	Progression Free Survival (PFS) Assessed According to RECIST Version 1.1		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)
Secondary	Duration of Response Assessed According to RECIST Version 1.1		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)