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A Study to Evaluate the Safety, Pharmacokinetics and Clinical Activity of RO6870810 and Atezolizumab (PD-L1 Antibody) in Participants With Advanced Ovarian Cancer or Triple Negative Breast Cancer

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ClinicalTrials.gov Identifier: NCT03292172
Recruitment Status : Suspended (Study on hold to evaluate safety and efficacy data)
First Posted : September 25, 2017
Last Update Posted : January 24, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
This is Phase IB, open label, non-randomized study designed to investigate the dose, safety, pharmacokinetics and anti-tumor activity of RO6870810 in combination with a fixed dose of atezolizumab. The study consists of four groups, Group 1 (Dose Escalation Group) and Group 2 (Sequential Dose Group), and Groups 3 and 4 (Expansion Groups), which will further evaluate the safety, pharmacokinetic, pharmacodynamic and preliminary clinical activity in patients with triple negaive breast cancer and/or ovarian cancer.

Condition or disease Intervention/treatment Phase
Advanced Ovarian Cancer Triple Negative Breast Cancer Drug: Atezolizumab Drug: RO6870810 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 116 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Open Label, Dose Finding and Expansion Phase IB Study to Evaluate the Safety, Pharmacokinetics and Clinical Activity of RO6870810 and Atezolizumab (Pd L1 Antibody) in Pateints With Advanced Ovarian Cancer or Triple Negative Breast Cancer
Actual Study Start Date : November 8, 2017
Estimated Primary Completion Date : January 16, 2021
Estimated Study Completion Date : January 16, 2021


Arm Intervention/treatment
Experimental: Group 1 - Escalation Dose: RO6870810 + Atezolizumab
Participants will be administered escalating doses of RO6870810 (0.3 milligram per kilogram [mg/kg], 0.45 mg/kg, and 0.65 mg/kg) subcutaneously (SC) once daily (QD) along with fixed dose of atezolizumab 1200 mg intravenously (IV) on Day 1 of each cycle (21 day cycles), every 3 weeks. RO6870810 will be given during the first 14 days.
Drug: Atezolizumab
Atezolizumab will be given intravenously (IV) at a fixed dose of 1200 mg on Day 1 of each cycle, every 3 weeks.

Drug: RO6870810
RO6870810 will be injected SC,at initial planned doses of 0.30, 0.45, or 0.65 mg/kg, QD for the first 14 days of a 21-day cycle.

Experimental: Group 2 - Sequential Dose: RO6870810 + Atezolizumab
Participants will be administered RO6870810 monotherapy (starting dose 0.30 mg/kg) during the first 14 days of 21-day Run-in period. Following the Run-in period, participants will continue to receive RO6870810 at the same dose in combination with fixed dose of atezolizumab 1200 mg IV every 3 weeks in 21-day cycles.
Drug: Atezolizumab
Atezolizumab will be given intravenously (IV) at a fixed dose of 1200 mg on Day 1 of each cycle, every 3 weeks.

Drug: RO6870810
RO6870810 will be injected SC,at initial planned doses of 0.30, 0.45, or 0.65 mg/kg, QD for the first 14 days of a 21-day cycle.

Experimental: Group 3 - Expansion in TNBC Group: RO6870810 + Atezolizumab
Participants will be administered dose of RO6870810 established in Group 1 (either 0.3 mg/kg, 0.45 mg/kg, or 0.65 mg/kg) SC QD along with fixed dose of atezolizumab 1200 mg IV on Day 1 of each cycle (21 day cycles), every 3 weeks. RO6870810 will be given during the first 14 days.
Drug: Atezolizumab
Atezolizumab will be given intravenously (IV) at a fixed dose of 1200 mg on Day 1 of each cycle, every 3 weeks.

Drug: RO6870810
RO6870810 will be injected SC,at initial planned doses of 0.30, 0.45, or 0.65 mg/kg, QD for the first 14 days of a 21-day cycle.

Experimental: Group 4 - Expansion in OC Group: RO6870810 + Atezolizumab
Participants will be administered dose of RO6870810 established in Group 1 (either 0.3 mg/kg, 0.45 mg/kg, or 0.65 mg/kg) SC QD along with fixed dose of atezolizumab 1200 mg IV on Day 1 of each cycle (21 day cycles), every 3 weeks. RO6870810 will be given during the first 14 days.
Drug: Atezolizumab
Atezolizumab will be given intravenously (IV) at a fixed dose of 1200 mg on Day 1 of each cycle, every 3 weeks.

Drug: RO6870810
RO6870810 will be injected SC,at initial planned doses of 0.30, 0.45, or 0.65 mg/kg, QD for the first 14 days of a 21-day cycle.




Primary Outcome Measures :
  1. Group 1: Percentage of Participants With Dose Limiting Toxicities (DLT) [ Time Frame: Cycle 1 (Day 21) ]
  2. Groups 1 to 4: Percentage of Participants With Adverse Events (AEs) [ Time Frame: Up to 22 months ]
  3. Groups 1 to 4: Percentage of Participants With Change in Vital Signs, Physical Findings, Electrocardiogram (ECG) and Laboratory Parameters [ Time Frame: Baseline up to follow-up visit (approximately 22 months) ]
  4. Groups 3 and 4: Objective Response (OR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. [ Time Frame: From first occurrence of objective response until disease progression or death from any cause (Up to 22 months) ]

Secondary Outcome Measures :
  1. Groups 1 to 4: Maximum concentration (Cmax) of RO6870810 (RO) and Atezolizumab (Ate) [ Time Frame: RO: Pre-dose Day 1,14,21;0.25,0.5,1,2,4,6,8,10hour (h) post-dose Day 14;24,28h post-dose Day 15 Run-in, Cycle 1, even cycles till end of treatment; Ate: pre-dose, end of infusion Day 1 Cycle 1; pre-dose Day 1 of even cycles; follow-up (Up to 22 months) ]
  2. Groups 1 to 4: Time of maximum concentration (tmax) of RO6870810 and Atezolizumab [ Time Frame: RO: Pre-dose Day 1,14,21;0.25,0.5,1,2,4,6,8,10hour (h) post-dose Day 14;24,28h post-dose Day 15 Run-in, Cycle 1, even cycles till end of treatment; Ate: pre-dose, end of infusion Day 1 Cycle 1; pre-dose Day 1 of even cycles; follow-up (Up to 22 months) ]
  3. Groups 1 to 4: Clearance (CL) or Apparent Clearance (CL/F) of RO6870810 and Atezolizumab [ Time Frame: RO: Pre-dose Day 1,14,21;0.25,0.5,1,2,4,6,8,10hour (h) post-dose Day 14;24,28h post-dose Day 15 Run-in, Cycle 1, even cycles till end of treatment; Ate: pre-dose, end of infusion Day 1 Cycle 1; pre-dose Day 1 of even cycles; follow-up (Up to 22 months) ]
  4. Groups 1 to 4: Volume of Distribution (Vd) or Apparent Volume of Distribution (Vd/F) of RO6870810 and Atezolizumab [ Time Frame: RO: Pre-dose Day 1,14,21;0.25,0.5,1,2,4,6,8,10hour (h) post-dose Day 14;24,28h post-dose Day 15 Run-in, Cycle 1, even cycles till end of treatment; Ate: pre-dose, end of infusion Day 1 Cycle 1; pre-dose Day 1 of even cycles; follow-up (Up to 22 months) ]
  5. Groups 1 to 4: Area Under the Plasma Concentration-Time Curve From Time Zero to End of the Dosing Interval (AUC0-tau) of RO6870810 and Atezolizumab [ Time Frame: RO: Pre-dose Day 1,14,21;0.25,0.5,1,2,4,6,8,10hour (h) post-dose Day 14;24,28h post-dose Day 15 Run-in, Cycle 1, even cycles till end of treatment; Ate: pre-dose, end of infusion Day 1 Cycle 1; pre-dose Day 1 of even cycles; follow-up (Up to 22 months) ]
  6. Groups 1 to 4: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of RO6870810 and Atezolizumab [ Time Frame: RO: Pre-dose Day 1,14,21;0.25,0.5,1,2,4,6,8,10hour (h) post-dose Day 14;24,28h post-dose Day 15 Run-in, Cycle 1, even cycles till end of treatment; Ate: pre-dose, end of infusion Day 1 Cycle 1; pre-dose Day 1 of even cycles; follow-up (Up to 22 months) ]
  7. Groups 1 to 4: Half life (t1/2) of RO6870810 and Atezolizumab [ Time Frame: RO: Pre-dose Day 1,14,21;0.25,0.5,1,2,4,6,8,10hour (h) post-dose Day 14;24,28h post-dose Day 15 Run-in, Cycle 1, even cycles till end of treatment; Ate: pre-dose, end of infusion Day 1 Cycle 1; pre-dose Day 1 of even cycles; follow-up (Up to 22 months) ]
  8. Groups 1 to 4: Trough concentration (Ctrough) of RO6870810 and Atezolizumab [ Time Frame: Pre-dose at Cycle 2 and at the beginning of every subsequent even-number cycles (Up to 22 months) ]
  9. Groups 1 and 2: Objective Response (OR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. [ Time Frame: From first occurrence of objective response until disease progression or death from any cause (Up to 22 months) ]
  10. Groups 1 to 4: Objective Response (OR) as per Immune-Modified RECIST [ Time Frame: From first occurrence of objective response until disease progression or death from any cause (Up to 22 months) ]
  11. Groups 1 to 4: Duration of Response (DoR) as per RECIST v1.1 and Immune-Modified RECIST [ Time Frame: From first occurrence of objective response until disease progression or death from any cause (Up to 22 months) ]
  12. Groups 1 to 4: Progression-Free Survival (PFS) per RECIST v1.1 and Immune-Modified RECIST [ Time Frame: From first occurrence of objective response until disease progression or death from any cause (Up to 22 months) ]
  13. Groups 1 to 4: Overall Survival (OS) [ Time Frame: From the time of first dose of study treatment to the time of death from any cause (Up to 22 months) ]
  14. Groups 1 to 4: Tumor Marker Assessments (CA-125, According to Modified Gynecologic Cancer InterGroup [GCIG] Guidelines,CEA, CA15-3 Changes) [ Time Frame: Day 1 of each cycle till end of treatment or disease progression or death from any cause (Up to 22 months) ]
  15. Groups 1 to 4: Changes in CD11b Expression Levels Measurement in CD14+ Monocytes From Blood Association with Steady-State RO6870810 PK Drug Exposure [ Time Frame: Day 1, 8, 15, 21 of Run-in period , Cycle 1 ]
  16. Groups 1 to 4: Changes in Markers (e.g., PD-L1, CD8/Ki 67) in Tissue Biopsy Specimens by Immunohistochemistry (IHC) [ Time Frame: Day 1, 15, 21 of Run-in period, Cycle 1 ]
  17. Groups 1 to 4: Groups 1 to 4: Percentage of Participants With Transcript Profiling Assessment Receiving Combination Study Treatment [ Time Frame: Pre-dose Day 1, 21 Run-in period, Cycle 1; 6h post-dose Day 1 Run-in period, Cycle 1 ]


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:-

  • Groups 1 and 2: Participants with histologically confirmed advanced ovarian cancer or triple negative breast cancer who in the opinion of the Investigator are appropriate for this study
  • Group 3: Participants with histologically confirmed TNBC who have received either one or 2 prior systemic treatments for metastatic breast cancer, and who have documented disease progression on or after the most recent treatment
  • Group 4: Recurrent ovarian cancer participant who have received no more than two prior lines of platinum therapy in the recurrent setting and have progressed within 9 months from the last platinum containing regimen
  • Measurable disease by RECIST criteria version 1.1 prior to study drug administration
  • Performance status of 0 or 1 on the eastern Cooperative Oncology Group (ECOG) scale
  • Life expectancy, in the opinion of the Investigator, of at least 3 months
  • Disease-free of active second/secondary or prior malignancies for => 2 years with the exception of squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast
  • Willing to provide the protocol specified tumor biopsies
  • Acceptable hematologic status, liver and renal function
  • Groups 1 and 2: Participants who have received prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, may be enrolled, provided the following requirements are met:

    • Minimum of 5 months from the last dose of anti-PD-1, anti-CTLA-4, anti-PD- L1 or CD137 agonist treatment
    • No history of severe immune-related adverse effects from CD137 agonist, anti−CTLA-4, anti-PD-1 or anti-PD-L1 (NCI CTCAE Grade 3 and 4). Any toxicity related to the therapy must have resolved completely, no residual toxicity as assessed by NCI CTCAE (v4.03)
  • Agree to use protocol defined methods of contraception - For all participants, the reliability of sexual abstinence must be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception

Exclusion Criteria:

  • Participants with history of prior malignancy except solid tumor treated curatively more than 3 years ago without evidence of recurrence
  • Asymptomatic or symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
  • History of leptomeningeal disease
  • Uncontrolled tumor-related pain
  • Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures. Participants with indwelling catheters are allowed.
  • Uncontrolled or symptomatic hypercalcemia
  • New York Heart Association Class III or IV cardiac disease, pericarditis, myocardial infarction within the past 6 months, unstable arrhythmia
  • Fredericia-corrected QT interval (QTcF) > 470 milli seconds (msec) (female) or > 450 msec (male), or history of congenital long QT syndrome. Any electrocardiogram (ECG) abnormality, including pericarditis, which in the opinion of the Investigator would preclude safe participation in the study.
  • Active, uncontrolled bacterial, viral, or fungal infections within 7 days of study entry requiring systemic therapy. Participants with active TB infection are excluded from the study.
  • Known clinically important respiratory impairment
  • History of major organ transplant
  • History of an autologous or allogeneic bone marrow transplant
  • Serious non-malignant disease that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor
  • Pregnant or nursing women
  • Any systemic anticancer therapy within 3 weeks prior to Cycle 1 Day 1
  • Any radiation treatment to metastatic site within <= 14 days of Cycle 1 Day 1
  • Major surgical procedure, open biopsy, or significant traumatic injury within 30 days prior to Cycle 1 Day 1 or anticipation of need for major surgical procedure during the course of the study
  • History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human or humanized antibodies or fusion proteins
  • Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
  • Active or history of autoimmune disease
  • History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
  • Positive test for Human immunodeficiency virus (HIV)
  • Active hepatitis B or hepatitis C
  • Receipt of a live, attenuated vaccine within 4 weeks prior to randomization or anticipation that such a live, attenuated vaccine will be required during the study
  • Treatment with investigational therapy within 28 days prior to initiation of study treatment
  • Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
  • Consumption of agents which strongly inhibit CYP3A4 enzyme, within 7 days prior to the first dose of study treatment and during the study
  • Consumption of agents which strongly induce CYP3A4 enzyme, within 14 days prior to the first dose of study treatment and during the study
  • Treatment with systemic immuno-stimulatory agents within 4 weeks or five half-lives of the drug (whichever is shorter) prior to the first dose of study treatment
  • Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to the first dose of study treatment, or, anticipated requirement for systemic immunosuppressive medications during the trial
  • History of allergic reactions attributed to components of the formulated product(s)
  • Unwillingness or inability to comply with procedures required in this protocol

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): NCT03292172


Locations
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United States, California
University of California San Diego
La Jolla, California, United States, 92093
UCLA Cancer Center
Santa Monica, California, United States, 90404
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Oklahoma
Oklahoma University Health Sciences Center
Oklahoma City, Oklahoma, United States, 73104
United States, Pennsylvania
University of Pennsylvania Health System; Cancer Center
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
Sarah Cannon Res Inst; TN Onc
Nashville, Tennessee, United States, 37203
Australia, New South Wales
St Vincent's Hospital Sydney
Darlinghurst, New South Wales, Australia, 2010
Australia, Victoria
Peter MacCallum Cancer Centre; Medical Oncology
Melbourne, Victoria, Australia, 3000
Canada, British Columbia
BCCA-Vancouver Cancer Centre
Vancouver, British Columbia, Canada, V5Z 4E6
Canada, Ontario
Hamilton Health Sciences - Juravinski Cancer Centre
Hamilton, Ontario, Canada, L8V 5C2
University Health Network; Princess Margaret Hospital; Medical Oncology Dept
Toronto, Ontario, Canada, M5G 2M9
Denmark
Rigshospitalet; Onkologisk Klinik
København Ø, Denmark, 2100
United Kingdom
Western General Hospital
Edinburgh, United Kingdom, EH4 2XU
Guys and St Thomas NHS Foundation Trust, Guys Hospital
London, United Kingdom, SE1 9RT
The Christie
Manchester, United Kingdom, M20 4BX
Churchill Hospital
Oxford, United Kingdom, OX3 7LJ
Sponsors and Collaborators
Hoffmann-La Roche

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT03292172     History of Changes
Other Study ID Numbers: NP39487
2017-001147-13 ( EudraCT Number )
First Posted: September 25, 2017    Key Record Dates
Last Update Posted: January 24, 2019
Last Verified: January 2019

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

Additional relevant MeSH terms:
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Breast Neoplasms
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Antibodies
Antibodies, Monoclonal
Atezolizumab
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents