Clinical Trials /

A Study of Atezolizumab Administered in Combination With Bevacizumab and/or With Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumors

NCT01633970

Description:

This open-label, Phase Ib study that has six treatment arms is designed to assess the safety, pharmacology and preliminary efficacy of atezolizumab (MPDL3280A; an engineered anti-programmed death-ligand 1 [PDL1] antibody) administered with bevacizumab (Arm A) and with bevacizumab plus oxaliplatin, leucovorin, and 5-fluorouracil (5-FU) (FOLFOX) (Arm B), with carboplatin and paclitaxel (Arm C), with carboplatin and pemetrexed (Arm D), with carboplatin and nab-paclitaxel (Arm E), and with nab-paclitaxel (Arm F) in participants with locally advanced or metastatic solid tumors. The study includes dose escalation cohort for establishing the maximum tolerated dose (MTD) or maximum administered dose (MAD) and then expansion cohort will be initiated based on a selected dose level at or below the MTD or MAD.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Breast Carcinoma
  • Colorectal Carcinoma
  • Fallopian Tube Carcinoma
  • Gastric Adenocarcinoma
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
  • Renal Cell Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of Atezolizumab Administered in Combination With Bevacizumab and/or With Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumors
  • Official Title:

Clinical Trial IDs

  • ORG STUDY ID: GP28328
  • SECONDARY ID: 2012-001422-10
  • NCT ID: NCT01633970

Conditions

  • Cancer

Interventions

DrugSynonymsArms
5-FUB: Atezolizumab + Bevacizumab + FOLFOX
AtezolizumabMPDL3280AA: Atezolizumab + Bevacizumab
BevacizumabAvastinA: Atezolizumab + Bevacizumab
CarboplatinC: Atezolizumab + Carboplatin + Paclitaxel
LeucovorinB: Atezolizumab + Bevacizumab + FOLFOX
Nab-paclitaxelE: Atezolizumab + Carboplatin + Nab-paclitaxel
OxaliplatinB: Atezolizumab + Bevacizumab + FOLFOX
PaclitaxelC: Atezolizumab + Carboplatin + Paclitaxel
PemetrexedD: Atezolizumab + Carboplatin + Pemetrexed

Purpose

This open-label, Phase Ib study that has six treatment arms is designed to assess the safety, pharmacology and preliminary efficacy of atezolizumab (MPDL3280A; an engineered anti-programmed death-ligand 1 [PDL1] antibody) administered with bevacizumab (Arm A) and with bevacizumab plus oxaliplatin, leucovorin, and 5-fluorouracil (5-FU) (FOLFOX) (Arm B), with carboplatin and paclitaxel (Arm C), with carboplatin and pemetrexed (Arm D), with carboplatin and nab-paclitaxel (Arm E), and with nab-paclitaxel (Arm F) in participants with locally advanced or metastatic solid tumors. The study includes dose escalation cohort for establishing the maximum tolerated dose (MTD) or maximum administered dose (MAD) and then expansion cohort will be initiated based on a selected dose level at or below the MTD or MAD.

Trial Arms

NameTypeDescriptionInterventions
A: Atezolizumab + BevacizumabExperimentalParticipants will receive atezolizumab 10 milligrams per kilogram (mg/kg) intravenous (IV) infusion (or a selected dose level not to exceed the single agent MTD or MAD determined in Study PCD4989g) with bevacizumab 15 mg/kg every 3 weeks (q3w). After establishment of MTD or MAD, participants will receive bevacizumab 15 mg/kg IV infusion on Day 1 of Cycle 1 followed by atezolizumab 1200 mg IV infusion q3w after Days 5-7 and then atezolizumab 1200 mg q3w and bevacizumab 15 mg/kg q3w on Day 1 of all subsequent cycles until disease progression or unacceptable toxicity.
  • Atezolizumab
  • Bevacizumab
B: Atezolizumab + Bevacizumab + FOLFOXExperimentalParticipants will receive FOLFOX IV infusion (oxaliplatin [85 milligrams per square meter {mg/m^2}], leucovorin [400 mg/m^2], 5-FU [400 mg/m^2]) on Day 1 of Cycle 1 and then atezolizumab 800 mg IV infusion every 2 weeks (q2w), bevacizumab 10 mg/kg IV infusion q3w and FOLFOX q2w on Day 1 of all subsequent cycles as per institutional guidelines until disease progression or unacceptable toxicity.
  • 5-FU
  • Atezolizumab
  • Bevacizumab
  • Leucovorin
  • Oxaliplatin
C: Atezolizumab + Carboplatin + PaclitaxelExperimentalParticipants will receive atezolizumab 1200 mg IV infusion q3w in combination with paclitaxel 200 mg/m^2 IV infusion q3w and then carboplatin IV q3w (on Day 1 of every 3-week cycle) to achieve an initial target area under the curve (AUC) of 6 milligrams per milliliter*minute (mg/mL*min) until disease progression or unacceptable toxicity.
  • Atezolizumab
  • Carboplatin
  • Paclitaxel
D: Atezolizumab + Carboplatin + PemetrexedExperimentalParticipants will receive atezolizumab 1200 mg IV infusion q3w in combination with premetrexed 500 mg/m^2 IV infusion q3w and then carboplatin IV q3w (on Day 1 of every 3-week cycle) to achieve an initial target AUC of 6 mg/mL*min until disease progression or unacceptable toxicity.
  • Atezolizumab
  • Carboplatin
  • Pemetrexed
E: Atezolizumab + Carboplatin + Nab-paclitaxelExperimentalParticipants will receive atezolizumab 1200 mg IV infusion q3w (on Day 1 of every 3-week cycle) in combination with nab-paclitaxel 100 mg/m^2 IV infusion once weekly (qw) (on Days 1, 8 and 15 of every 3-week cycle) and then carboplatin IV infusion q3w (on Day 1 of every 3-week cycle) to achieve an initial target AUC of 6 mg/mL*min until disease progression or unacceptable toxicity.
  • Atezolizumab
  • Carboplatin
  • Nab-paclitaxel
F: Atezolizumab + Nab-paclitaxelExperimentalParticipants will receive atezolizumab 800 mg IV infusion q2w (Days 1 and 15) in combination with nab-paclitaxel 125 mg/m^2 IV infusion qw (on Days 1, 8 and 15 of every 3-week cycle) until disease progression or unacceptable toxicity.
  • Atezolizumab
  • Nab-paclitaxel

Eligibility Criteria

        Inclusion Criteria:

        General Inclusion Criteria:

          -  Histologically or cytologically documented advanced solid tumors

          -  Adequate hematologic and end organ function

          -  Measurable disease by RECIST v1.1

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

          -  Resolution of any acute, clinically significant treatment-related toxicity from prior
             therapy to Grade less than or equal to (</=) 1 prior to study entry, with the
             exception of alopecia

        Eligible Tumor Types:

        Arm A Escalation Cohorts and Arms A and B Biopsy Cohort (Cutaneous/Subcutaneous Lesions)

          -  Histologically or cytologically documented, incurable or metastatic solid malignancy
             that has failed all available or acceptable standard therapy for which the participant
             is eligible Arm A and B Safety Expansion Cohorts, Arm B Escalation Cohorts, and Arm B
             Biopsy Cohort (Liver Lesions)

          -  Histologically or cytologically confirmed metastatic colorectal cancer (mCRC).
             Participants in the Arm A Safety Expansion Cohort must have mCRC for which established
             therapies have proved ineffective or intolerable. Participants with malignancies other
             than mCRC within 5 years prior to Day 1 (except for those with a negligible risk of
             metastasis or death, such as adequately treated carcinoma in situ of the cervix, basal
             or squamous cell skin cancer, localized prostate cancer treated surgically with
             curative intent, or ductal carcinoma in situ treated surgically with curative intent)
             are not eligible.

        Arm A renal cell carcinoma (RCC) Cohort:

        - Histologically or cytologically confirmed advanced or metastatic RCC with a clear cell
        component.

        Arm A Tumor Type-Specific Cohort:

        Gastric Cancer:

        - Histologically or cytologically confirmed locally advanced or metastatic adenocarcinoma
        of the stomach or gastroesophageal junction for which established therapies have proved
        ineffective or intolerable. The decision may be made to restrict enrollment to participants
        with a specified tumor PD-L1 status (e.g., immunohistochemistry [IHC] status 0/1 or 2/3)

        Ovarian Cancer:

        - Measurable/assessable ovarian cancer (defined as epithelial ovarian, fallopian tube, or
        primary peritoneal cancer) that has progressed less than (<) 6 months after completing
        platinum-based therapy. The following histological types are eligible: Adenocarcinoma NOS,
        clear cell adenocarcinoma, endometriod adenocarcinoma, malignant Brenner's tumour, mixed
        epithelial carcinoma, mucinous adenocarcinoma, serous adenocarcinoma, transitional cell
        carcinoma, undifferentiated carcinoma

        Bladder Cancer:

          -  Histologically or cytologically documented locally advanced (T4b, any N; or any T, N
             2-3) or metastatic (M1, Stage IV) transitional cell carcinoma of the urothelium
             (including renal pelvis, ureters, urinary bladder, urethra)

          -  Participants with mixed histologies are required to have a dominant transitional cell
             pattern

          -  Locally advanced bladder cancer must be inoperable based on involvement of pelvic
             sidewall or adjacent viscera (clinical stage T4b) or bulky nodal metastasis (N2-N3)

          -  Disease progression during or following treatment with at least one
             platinum-containing regimen (e.g., GC, MVAC, CarboGem, etc.) for inoperable locally
             advanced or metastatic urothelial carcinoma or disease recurrence

        Cervical Cancer:

          -  Persistent or recurrent squamous cell carcinoma of the cervix (including adenosquamous
             tumors)

        Arms C, D, and E Cohorts:

        - Histologically or cytologically documented Stage IIIB (not eligible for definitive
        chemoradiotherapy), Stage IV, or recurrent non-small cell lung cancer (NSCLC)

        Arm F Cohort:

          -  Histologically confirmed estrogen receptor (ER)-, progesterone receptor (PR)-, and
             human epidermal growth factor receptor (HER)-negative (triple-negative) adenocarcinoma
             of the breast that has been treated with systemic cytotoxic therapy. Locally recurrent
             disease must not be amenable to resection with curative intent

          -  Participants with tumors amenable to excisional, punch, or core needle biopsy are
             eligible for a separate biopsy expansion cohort

        Tumor molecular status:

        Arm A safety expansion cohort

        - Up to 10 participants with CRC and high microsatellite instability (MSI-H) may be
        enrolled

        Exclusion Criteria:

        General Exclusions

          -  Any approved anti-cancer therapy, including chemotherapy, hormonal therapy,
             radiotherapy, or herbal therapy intended as anti-cancer therapy, within 3 weeks prior
             to initiation of study treatment; the following are allowed: hormonal therapy with
             gonadotropin-releasing hormone agonists or antagonists for prostate cancer,
             hormone-replacement therapy, and palliative radiotherapy for bone metastases greater
             than (>) 2 weeks prior to Day 1

          -  Bisphosphonate therapy for symptomatic hypercalcemia

          -  Known clinically significant liver disease

          -  Known primary central nervous (CNS) malignancy or active CNS metastases (progressing
             or requiring anticonvulsants or corticosteroids for symptomatic control)

          -  Pregnant or lactating women

          -  Known hypersensitivity to Chinese hamster ovary cell products or any component of the
             atezolizumab formulation

          -  History of autoimmune disease, idiopathic pulmonary fibrosis, human immunodeficiency
             virus (HIV), hepatitis B or C infection; history of hepatitis B is allowed if
             infection has resolved (absence of hepatitis B surface antigen [HBsAg])

          -  Severe infections within 4 weeks prior to Day 1, or signs or symptoms of significant
             infection within 2 weeks prior to Day 1

          -  Received oral or IV antibiotics within 2 weeks prior to Cycle 1 Day 1

          -  History of myocardial infarction, unstable angina stroke or transient ischemic attack
             within 6 months prior to Day 1

          -  Administration of a live, attenuated vaccine within 4 weeks before Day 1 or
             anticipation that such a live attenuated vaccine will be required during the study
             Bevacizumab-Specific Exclusions (Arms A and B) Exclusion Criteria Unique to Arm A RCC
             Cohort

          -  Any prior systemic treatment (including tyrosine kinase inhibitors, antibody therapy,
             immunotherapy, chemotherapy, hormonal therapy, or investigational therapy) for RCC.
             All treatments, neo-adjuvant, adjuvant, or for locally advanced or metastatic RCC are
             not permitted

        Arm A Tumor Type-Specific Cohort:

        Gastric Cancer:

        - Prior approved or experimental anti-vascular endothelial growth factor or its receptor
        (VEGF/VEGFR) therapy (including, for example, bevacizumab or nintedanib). The decision may
        be made to allocate a specified number of slots to participants who have received prior
        anti-VEGF/VEGFR therapy

        Ovarian Cancer:

          -  Refractory disease

          -  History of bowel obstruction

          -  >2 prior anticancer regimens

          -  Prior approved or experimental anti-VEGF/VEGFR therapy (including, for example,
             bevacizumab or nintedanib)

        Cervical Cancer:

        - > 2 prior cytotoxic regimens, not including prior cisplatin-based chemotherapy
        concomitantly administered with primary pelvic radiation

        Exclusion Criteria Unique to Arm B:

          -  Prior treatment with an oxaliplatin-containing regimen. Oxaliplatin >12 months prior
             to the diagnosis of metastatic disease is permitted.

          -  Known dihydropyrimidine dehydrogenase deficiency or thymidylate synthase gene
             polymorphism predisposing the participant for 5-FU toxicity

        Exclusion Criteria Unique to Arms C, D, and E:

          -  Prior chemotherapy for locally advanced or metastatic NSCLC

          -  For participants who received prior adjuvant/neo-adjuvant chemotherapy or
             chemoradiation for NSCLC, a treatment-free interval >6 months between the last
             treatment administration and the date of recurrence in required

          -  Participants with a known epidermal growth factor receptor (EGFR) sensitizing mutation
             must have experienced disease progression during or after treatment with an approved
             EGFR tyrosine kinase inhibitor

          -  Participants with a known anaplastic lymphoma kinase (ALK) fusion oncogene must have
             experienced disease progression during or after treatment with crizotinib

          -  For Arm D (carboplatin + pemetrexed), squamous cell histology or evidence of mixed
             NSCLC histology with a predominance of the squamous cell type

          -  For Arm D (carboplatin + pemetrexed), inability to discontinue treatment with
             non-steroidal anti-inflammatory drugs (NSAIDs) for 5 days

        Exclusion Criteria Unique to Arm F:

          -  Prior therapy with more than two cytotoxic regimens for metastatic or locally advanced
             triple-negative breast cancer (TNBC)

          -  Treatment with a taxane-containing regimen within 6 months before enrollment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Atezolizumab Dose
Time Frame:Days 1-21 of Cycle 1 (Cycle length = 21 days) for Arms A, C, D and E and the 28 days following the first administration of atezolizumab in Arm B
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Duration of Objective Response According to irRC
Time Frame:From Baseline until death or disease progression, whichever occurs first (up to approximately 5 years)
Safety Issue:
Description:
Measure:Progression-Free Survival According to RECIST v1.1
Time Frame:From Baseline until death or disease progression, whichever occurs first (up to approximately 5 years)
Safety Issue:
Description:
Measure:Progression-Free Survival According to irRC
Time Frame:Baseline until death or disease progression, whichever occurs first (up to approximately 5 years)
Safety Issue:
Description:
Measure:Pharmacokinetics: Area Under the Serum Concentration-Time Curve (AUC) of Atezolizumab
Time Frame:Pre-infusion (0 hour [hr]) on Cycle 1 Day 1 (cycle length = 21 or 14 days) up to approximately 5 years (detailed timeframe is provided in outcome measure description)
Safety Issue:
Description:
Measure:Pharmacokinetics: Maximum Serum Concentration (Cmax) of Atezolizumab
Time Frame:Pre-infusion (0 hr) on Cycle 1 Day 1 (cycle length = 21 or 14 days) up to approximately 5 years (detailed timeframe is provided in outcome measure description)
Safety Issue:
Description:
Measure:Minimum Serum Concentration (Cmin) of Atezolizumab
Time Frame:Pre-infusion (0 hr) on Cycle 1 Day 1 (cycle length = 21 or 14 days) up to approximately 5 years (detailed timeframe is provided in outcome measure description)
Safety Issue:
Description:
Measure:Percentage of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Time Frame:From Baseline until death or disease progression, whichever occurs first (up to approximately 5 years)
Safety Issue:
Description:
Measure:Percentage of Participants With Best Overall Response According to Immune-Related Response Criteria (irRC)
Time Frame:From Baseline until death or disease progression, whichever occurs first (up to approximately 5 years)
Safety Issue:
Description:
Measure:Percentage of Participants With Objective Response (Complete Response + Partial Response) According to RECIST v1.1
Time Frame:From Baseline until death or disease progression, whichever occurs first (up to approximately 5 years)
Safety Issue:
Description:
Measure:Percentage of Participants With Objective Response (Complete Response + Partial Response) According to irRC
Time Frame:From Baseline until death or disease progression, whichever occurs first (up to approximately 5 years)
Safety Issue:
Description:
Measure:Duration of Objective Response According to RECIST v1.1
Time Frame:From Baseline until death or disease progression, whichever occurs first (up to approximately 5 years)
Safety Issue:
Description:
Measure:Pharmacokinetics: Clearance of Atezolizumab
Time Frame:Pre-infusion (0 hr) on Cycle 1 Day 1 (cycle length = 21 or 14 days) up to approximately 5 years (detailed timeframe is provided in outcome measure description)
Safety Issue:
Description:
Measure:Pharmacokinetics: Volume of Distribution of Atezolizumab
Time Frame:Pre-infusion (0 hr) on Cycle 1 Day 1 (cycle length = 21 or 14 days) up to approximately 5 years (detailed timeframe is provided in outcome measure description)
Safety Issue:
Description:
Measure:Pharmacokinetics: Accumulation Ratio of Atezolizumab
Time Frame:Pre-infusion (0 hr) on Cycle 1 Day 1 (cycle length = 21 or 14 days) up to approximately 5 years (detailed timeframe is provided in outcome measure description)
Safety Issue:
Description:
Measure:Pharmacokinetics: Half-Life of Atezolizumab
Time Frame:Pre-infusion (0 hr) on Cycle 1 Day 1 (cycle length = 21 or 14 days) up to approximately 5 years (detailed timeframe is provided in outcome measure description)
Safety Issue:
Description:
Measure:Pharmacokinetics: Cmax of Bevacizumab
Time Frame:Pre-infusion (0 hr), 0.5 hrs after EOI (infusion duration=90 min) on Day 1 Cycles 1 & 3 (each cycle = 21 days); EOT; every 30 days (for up to 120 days) after EOT until death or withdrawal or study closure (up to approximately 5 years)
Safety Issue:
Description:
Measure:Pharmacokinetics: Cmin of Bevacizumab
Time Frame:Pre-infusion (0 hr), 0.5 hrs after EOI (infusion duration=90 min) on Day 1 Cycles 1 & 3 (each cycle = 21 days); EOT; every 30 days (for up to 120 days) after EOT until death or withdrawal or study closure (up to approximately 5 years)
Safety Issue:
Description:
Measure:Maximum Plasma Concentration of 5-FU
Time Frame:Pre- infusion (0 hr) on Day 1 Cycle 1; end of 5-FU bolus and 2 and 12-24 hrs after end of 5-FU bolus (infusion duration = 46 hrs) on Day 1 of Cycles 1 and 3 (each cycle=14 days)
Safety Issue:
Description:
Measure:Pharmacokinetics: Maximum Plasma Concentration of Oxaliplatin
Time Frame:Pre-infusion (0 hr) on Day 1 Cycle 1; 5-10 min before end of oxaliplatin infusion (infusion duration = 120 min) and 2 and 12-24 hrs after end of 5-FU bolus (infusion duration = 46 hrs) on Day 1 of Cycles 1 and 3 (each cycle=14 days)
Safety Issue:
Description:
Measure:Pharmacokinetics: Maximum Plasma Concentration of Carboplatin
Time Frame:Pre-infusion (0 hr), 5-10 min before and 1 hr after carboplatin EOI (infusion duration=15-30 min),24 hr after atezolizumab EOI (infusion duration=90 min)on Day 1 Cycle 1; 5-10 min before and 1 hr after carboplatin EOI Day 1 Cycle 3 (each cycle=21 days)
Safety Issue:
Description:
Measure:Maximum Plasma Concentration of Paclitaxel
Time Frame:Pre-infusion (0 hr), 5-10 min before and 1 hr after paclitaxel EOI (infusion duration=180 min), 24 hr after atezolizumab EOI (infusion duration=90 min) on Day 1 Cycle 1; 5-10 min before and 1 hr after paclitaxel EOI on Day 1 Cycle 3 (each cycle=21 days)
Safety Issue:
Description:
Measure:Pharmacokinetics: Maximum Plasma Concentration of Pemetrexed
Time Frame:Pre-infusion (0 hr), 5-10 min before and 1 hr after pemetrexed EOI (infusion duration=10 min), 24 hr after atezolizumab EOI (infusion duration=90 min) on Day 1 Cycle 1; 5-10 min before and 1 hr after pemetrexed EOI on Day 1 Cycle 3 (each cycle = 21 days)
Safety Issue:
Description:
Measure:Maximum Plasma Concentration of Nab-Paclitaxel (Total Paclitaxel)
Time Frame:Pre-infusion (0 hr), 5-10 min before and 1 hr after nab-paclitaxel EOI (infusion duration=30 min) on Day 1 of Cycles 1 and 3; 24 hr after atezolizumab EOI (infusion duration=90 min) on Day 1 Cycle 1 (each cycle=7 days)
Safety Issue:
Description:
Measure:Number of Cycles of Each Component of Treatment Administer
Time Frame:From Baseline up to approximately 5 years
Safety Issue:
Description:
Measure:Dose Intensity of Each Component of Treatment Administer
Time Frame:From Baseline up to approximately 5 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Genentech, Inc.

Last Updated

January 8, 2018