TLR8 Agonist VTX-2337 and Pegylated Liposomal Doxorubicin Hydrochloride or Paclitaxel in Treating Patients With Recurrent or Persistent Ovarian Epithelial, Fallopian Tube, or Peritoneal Cavity Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Gynecologic Oncology Group
ClinicalTrials.gov Identifier:
NCT01294293
First received: February 10, 2011
Last updated: August 8, 2014
Last verified: August 2014
  Purpose

This phase I trial is studying the side effects and best dose of TLR8 agonist VTX-2337 and pegylated liposomal doxorubicin hydrochloride in treating patients with recurrent or persistent ovarian epithelial, fallopian tube, or peritoneal cavity cancer. Biological therapies, such as TLR8 agonist VTX-2337, may stimulate the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as pegylated liposomal doxorubicin hydrochloride and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving TLR8 agonist VTX-2337 together with pegylated liposomal doxorubicin hydrochloride or paclitaxel may kill more tumor cells.


Condition Intervention Phase
Brenner Tumor
Ovarian Clear Cell Cystadenocarcinoma
Ovarian Endometrioid Adenocarcinoma
Ovarian Mixed Epithelial Carcinoma
Ovarian Mucinous Cystadenocarcinoma
Ovarian Serous Cystadenocarcinoma
Ovarian Undifferentiated Adenocarcinoma
Recurrent Fallopian Tube Cancer
Recurrent Ovarian Epithelial Cancer
Recurrent Primary Peritoneal Cavity Cancer
Drug: TLR8 agonist VTX-2337
Other: diagnostic laboratory biomarker analysis
Other: pharmacological study
Drug: pegylated liposomal doxorubicin hydrochloride
Drug: paclitaxel
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of VTX-2337 in Combination With Pegylated Liposomal Doxorubicin (PLD; NSC# 712227) or in Combination With Weekly Pactilaxel (NSC #673089) in Patients With Recurrent or Persistent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer

Resource links provided by NLM:


Further study details as provided by Gynecologic Oncology Group:

Primary Outcome Measures:
  • First-cycle dose-limiting toxicities [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Frequency and severity of toxicities as assessed by CTCAE [ Time Frame: Up to 1 year ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Immune activation (e.g., Th1, cytokines) [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Immune response endpoints (e.g., Th1 cytokines) will be summarized with simple descriptive statistics and analyzed with linear mixed models accounting for the longitudinal aspect of the data.

  • Pharmacokinetic measures of TLR8 agonist VTX-2337 [ Time Frame: Baseline, 0.5, 2, 4, 8, and 24 hours after TLR8 agonist VTX-2337 injection ] [ Designated as safety issue: No ]
  • Pharmacokinetic measures of pegylated liposomal doxorubicin hydrochloride [ Time Frame: Baseline, 0.5, 2, 4, 8, and 24 hours after TLR8 agonist VTX-2337 injection ] [ Designated as safety issue: No ]
  • Pharmacokinetic measures of paclitaxel [ Time Frame: Baseline, 0.5, 2, 4, 8, and 24 hours after TLR8 agonist VTX-2337 injection ] [ Designated as safety issue: No ]

Estimated Enrollment: 36
Study Start Date: March 2011
Estimated Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (TLR8 agonist VTX-2337, PLD, and Paclitaxel)
Patients receive TLR8 agonist VTX-2337 SC on days 3, 10, and 17 and pegylated liposomal doxorubicin hydrochloride IV over 60 minutes on day 1 or TLR8 agonist VTX-2337 SC on days 1, 8, and 15 and paclitaxel IV over 60 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: TLR8 agonist VTX-2337
Given SC
Other Names:
  • Toll-like receptor 8 agonist VTX-2337
  • VTX-2337
Other: diagnostic laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Drug: pegylated liposomal doxorubicin hydrochloride
Given IV
Other Names:
  • CAELYX
  • Dox-SL
  • DOXIL
  • doxorubicin hydrochloride liposome
  • LipoDox
Drug: paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • TAX
  • Taxol

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated doses (MTD) and dose limiting toxicities (DLTs) of VTX-2337 when administered in combination with pegylated liposomal doxorubicin (PLD; Doxil, Lipodox™) 40 mg/m2 in Regimen 1 and when administered in combination with weekly paclitaxel 80 mg/m2 in Regimen 2, and the associated DLTs based on adverse events that occur in cycle 1 for each of these combinations in women with recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer.

II. To examine the tolerability of the combination at the MTD of VTX-2337 assessed in combination with PLD 40 mg/m2 and with PLD 50 mg/m2 in Regimen 1 and in combination with weekly paclitaxel in Regimen 2.

III. To determine recommended phase II doses (RP2D) of VTX-2337 in combination with PLD in Regimen 1 and in combination with weekly paclitaxel in Regimen 2.

SECONDARY OBJECTIVES:

I. To assess the biological effects (immune activation) of VTX-2337 in combination with PLD in Regimen 1 and in combination with weekly paclitaxel in Regimen 2.

II. To assess the pharmacokinetics in patients receiving VTX-2337 in combination with PLD in Regimen 1 and in combination with weekly paclitaxel in Regimen 2.

III. To assess the tolerability (including CTCAE v4 Grade 3/4 allergic reaction) of weekly paclitaxel 80 mg/m2 when administered without corticosteroid premedication (Regimen 2 only).

TERTIARY OBJECTIVES:

I. To assess the anti-tumor activity of VTX-2337 when administered concomitantly with PLD in Regimen 1 and when administered concomitantly with weekly paclitaxel in Regimen 2 in patients with recurrent or persistent epithelial ovarian fallopian tube or primary peritoneal cancer.

II. To assess the effect of TLR8 polymorphisms on the biological (immune) and clinical effects of VTX-2337 in combination with PLD in Regimen 1 and in combination with weekly paclitaxel in Regimen 2.

OUTLINE: This is a multicenter, dose-escalation study.

Patients receive TLR8 agonist VTX-2337 subcutaneously (SC) on days 3, 10, and 17 and pegylated liposomal doxorubicin hydrochloride IV over 60 minutes on day 1 or TLR8 agonist VTX-2337 subcutaneously on days 1, 8, and 15 and paclitaxel IV over 60 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Blood samples are collected periodically during courses 1 and 2 for pharmacokinetic, pharmacogenomic, and other research studies. After completion of study treatment, patients are followed up every 3 months for 1 year.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma

    • Histologic documentation of the original primary tumor is required via the pathology report
  • Patients with the following histologic cell types are eligible:

    • Serous adenocarcinoma
    • Endometrioid adenocarcinoma
    • Mucinous adenocarcinoma
    • Undifferentiated carcinoma
    • Clear cell adenocarcinoma
    • Mixed epithelial adenocarcinoma
    • Transitional cell carcinoma
    • Malignant Brenner tumor
    • Adenocarcinoma not otherwise specified (N.O.S.)
  • Patient must have measurable disease or detectable (non-measurable) disease:

    • Measurable disease will be defined by RECIST 1.1

      • Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded)
      • Each lesion must be ≥ 10 mm when measured by CT, MRI, or caliper measurement by clinical exam or ≥ 20 mm when measured by chest x-ray
      • Lymph nodes must be ≥ 15 mm in short axis when measured by CT or MRI
    • Detectable (non-measurable) disease is defined as not having measurable disease but has at least one of the following conditions:

      • Baseline values of CA-125 ≥ 2 x ULN

        • Patients whose CA-125 is < 100 U/mL must undergo a second confirmatory value within a period of ≤ 4 weeks
        • Patients with a level ≥ 100 U/mL may be entered without confirmatory measurement
        • The CA-125 assessment for eligibility must be done at least 4 weeks after paracentesis or other surgical procedures
      • Solid and/or cystic abnormalities on radiographic imaging that do not meet RECIST 1.1 definitions for target lesions
    • Patient with measurable disease must have at least one "target lesion" to be used to assess response on this protocol as defined by RECIST 1.1

      • Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy
  • Patients must have had one prior platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound; this initial treatment may have included intraperitoneal therapy, consolidation, non-cytotoxic agents or extended therapy administered after surgical or non-surgical assessment

    • For patients enrolled in Regimen 2, weekly paclitaxel, treatment for their primary disease must have included paclitaxel; this can have been given weekly or every 3 weeks; patients who experienced severe hypersensitivity to paclitaxel are excluded
    • Patients are allowed to receive, but are not required to receive, two additional cytotoxic regimens for management of recurrent or persistent disease, with no more than 1 non-platinum, non-taxane regimen

      • For patients enrolled in Regimen 1 which includes PLD, prior treatment with PLD is NOT allowed
      • For patients enrolled in Regimen 2 which includes weekly paclitaxel, prior treatment with weekly paclitaxel for recurrent or persistent disease is NOT allowed
    • Patients are allowed to receive, but are not required to receive, non-cytotoxic therapy (such as bevacizumab) as part of their primary treatment regimen; patients are allowed to receive, but are not required to receive, non-cytotoxic therapy for management of recurrent or persistent disease
    • Patients who have received only one prior cytotoxic regimen (platinum-based regimen for management of primary disease), must have a platinum-free interval of less than 12 months, or have progressed during platinum-based therapy, or have persistent disease after a platinum-based therapy
  • No patients with history or evidence upon physical examination of CNS disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA), or subarachnoid hemorrhage within six months of the first date of treatment on this study
  • No patients who have received oral or parenteral corticosteroids within 2 weeks of study entry or who require ongoing systemic immunosuppressive therapy for any reason
  • Patients must have a GOG performance status of 0 or 1
  • Absolute neutrophil count (ANC) ≥ 1,500/mm^3; this ANC cannot have been induced or supported by granulocyte colony-stimulating factors
  • Platelets ≥ 100,000/mm^3
  • Hemoglobin ≥ 9 g/dL
  • Creatinine ≤ 1.5 x institutional upper limit normal (ULN)
  • Bilirubin ≤ 1.5 x ULN
  • SGOT (AST) ≤ 3.0 x ULN
  • Alkaline phosphatase ≤ 2.5 x ULN
  • Neuropathy (sensory and motor) less than or equal to grade 1
  • Not pregnant or nursing
  • Negative pregnancy test
  • Patients of childbearing potential must be practicing an effective form of contraception
  • Patients should be free of active infection requiring parenteral antibiotics
  • No patients with active autoimmune disease

    • "Active" refers to any condition currently requiring therapy
    • Examples of autoimmune disease include systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis
  • Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer or localized cancer of the breast, head and neck, or skin, are excluded if there is any evidence of other malignancy being present within the last three years
  • No patients with known chronic or active hepatitis
  • No patients with clinically significant cardiovascular disease, this includes:

    • Uncontrolled hypertension, defined as systolic > 140 mm Hg or diastolic > 90 mm Hg
    • Myocardial infarction or unstable angina within 6 months of the first date of treatment on this study
    • History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) or cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled with anti-arrhythmic medication)
    • QTc interval ≥ 450 ms on baseline ECG
    • Baseline ejection fraction ≤ 50% as assessed by echocardiogram or MUGA
    • New York Heart Association (NYHA) class II or higher congestive heart failure
    • Grade 2 or higher peripheral ischemia (brief [< 24 hours] episode of ischemia managed non-surgically and without permanent deficit)
  • No patients with clinical symptoms or signs of gastrointestinal obstruction and who require parenteral hydration or nutrition
  • Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration

    • Continuation of hormone replacement therapy is permitted
  • No patients who have had previous treatment with VTX-2337, pegylated liposomal doxorubicin, doxorubicin, or any other anthracycline
  • Patients are excluded if their previous cancer treatment contraindicates this protocol therapy
  • Patients are allowed to receive, but are not required to receive, two additional cytotoxic regimens for management of recurrent or persistent disease, with no more than 1 non-platinum, non-taxane regimen (prior treatment with pegylated liposomal doxorubicin is NOT allowed)
  • Patients are allowed to receive, but are not required to receive, non-cytotoxic therapy (such as bevacizumab) as part of their primary treatment regimen
  • Patients are allowed to receive, but are not required to receive, non-cytotoxic therapy for management of recurrent or persistent disease
  • Patients must have recovered from effects of recent surgery, radiotherapy, or chemotherapy
  • Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis OTHER THAN for the treatment of ovarian, fallopian tube, or primary peritoneal cancer within the last three years are excluded

    • Prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease
  • Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER THAN for the treatment of ovarian, fallopian tube or primary peritoneal cancer within the last three years are excluded

    • Patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease
  • No patients who have received an investigational agent within 30 days of study entry
  • Any other prior therapy directed at the malignant tumor, including biological and immunologic agents, must be discontinued at least three weeks prior to registration
  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: NCT01294293

Locations
United States, Arizona
Gynecologic Oncology Group of Arizona
Phoenix, Arizona, United States, 85012
Saint Joseph's Hospital and Medical Center
Phoenix, Arizona, United States, 85013
United States, Colorado
University of Colorado Cancer Center - Anschutz Cancer Pavilion
Aurora, Colorado, United States, 80045
United States, Iowa
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States, 52242
United States, Kentucky
University of Kentucky
Lexington, Kentucky, United States, 40536
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
United States, Ohio
MetroHealth Medical Center
Cleveland, Ohio, United States, 44109
United States, Oklahoma
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States, 73104
United States, Pennsylvania
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States, 19111
United States, Rhode Island
Women and Infants Hospital
Providence, Rhode Island, United States, 02905
Sponsors and Collaborators
Gynecologic Oncology Group
Investigators
Principal Investigator: Bradley Monk Gynecologic Oncology Group
  More Information

No publications provided

Responsible Party: Gynecologic Oncology Group
ClinicalTrials.gov Identifier: NCT01294293     History of Changes
Other Study ID Numbers: GOG-9925, NCI-2011-02663, CDR0000695034, GOG-9925, GOG-9925, U10CA027469
Study First Received: February 10, 2011
Last Updated: August 8, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Adenocarcinoma
Neoplasms, Glandular and Epithelial
Ovarian Neoplasms
Fallopian Tube Neoplasms
Peritoneal Neoplasms
Cystadenocarcinoma
Carcinoma
Carcinoma, Endometrioid
Cystadenocarcinoma, Serous
Cystadenocarcinoma, Mucinous
Brenner Tumor
Neoplasms by Histologic Type
Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Fallopian Tube Diseases
Abdominal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Peritoneal Diseases
Neoplasms, Cystic, Mucinous, and Serous
Endometrial Neoplasms
Uterine Neoplasms

ClinicalTrials.gov processed this record on October 02, 2014