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Title A Phase 1B study of PF-05082566 in combination with Mogamulizumab (KW-0761) in patients with advanced solid tumors

IRB PFIZ1Y15

CC 15-667

Hospital Main Campus

Phase Phase 1

Disease Solid Tumors

Drug Mogamulizumab , PF-05082566

Description

Primary Objective

• To estimate the Maximum Tolerated Dose (MTD) and select the Recommended Phase 2 Dose (RP2D) of PF-05082566 in combination with mogamulizumab in patients with advanced solid tumors.

Secondary Objectives

• To evaluate the overall safety profile;
• To characterize the pharmacokinetics (PK) of PF-05082566 and mogamulizumab when given in combination;
• To evaluate the immunogenicity of PF-05082566 and mogamulizumab when given in combination;
• To document any anti-tumor activity.

Exploratory Objectives

• To evaluate the pharmacodynamic effect of PF-05082566 and mogamulizumab on immune parameters in peripheral blood (lymphocyte subpopulations, serum biomarkers, and gene expression) and tumor tissue.
• To characterize the mechanism of sensitivity and/or resistance to PF-05082566 in combination with mogamulizumab in tumor tissue (expansion cohorts only).

Inclusion Criteria

1. Histological or cytological diagnosis of advanced/metastatic solid tumor malignancy (preferably, colorectal, head and neck, NSCLC, bladder, and ovarian carcinomas) which has progressed on standard therapy, or for which no standard therapy is available.
2. Measurable disease by RECIST version 1.1.
3. For Expansion Cohorts only: patients must have tumor accessible for biopsies (core needle biopsy or excision preferred).
4. Age ≥18 years.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Adequate bone marrow function, defined as follows:
   • absolute neutrophil count (ANC) ≥1.5 x 10⁹/L (≥1,500/μL);
   • platelet (PLT) count ≥100 x 10⁹/L (≥100,000/μL),
   • hemoglobin (Hb) ≥9.0 g/dL (≥5.6 mmol/L).

   Patients must be transfusion independent (ie, no blood product transfusions for a period of at least 14 days prior to study registration).

7. Adequate renal function, including:
   • serum creatinine ≤1.5 x upper limit of normal (ULN) OR
   • estimated creatinine clearance ≥60 mL/min as calculated using the method standard for the institution.
8. Adequate liver function, including:
   • Total serum bilirubin ≤1.5 x ULN (unless the patient has documented Gilbert syndrome);
   • Aspartate and Alanine transaminase (AST & ALT) ≤2.5 x ULN;
   • Alkaline phosphatase ≤2.5 x ULN; (≤5 x ULN in case of bone metastasis).
9. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1 except for AEs not constituting a safety risk by investigator judgment.
10. Serum/urine pregnancy test (for females of childbearing potential) negative at screening and before the patient will receive the study treatment.
11. Male and female patients of childbearing potential and at risk for pregnancy must agree to use two (2) highly effective methods of contraception throughout the study and for 60 days after the last dose of assigned study treatment.
12. Female patients who are not of childbearing potential (ie, meet at least one of the following criteria):
    • Have undergone a documented hysterectomy and/or bilateral oophorectomy;
    • Have medically confirmed ovarian failure; OR
    • Achieved post-menopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal women.
13. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
14. Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory tests and other procedures.

Exclusion Criteria

1. Central nervous system primary malignancies, active seizure disorder or spinal cord compression, or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to registration and any neurologic symptoms have returned to baseline), have no evidence of new or progressing brain metastases. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
2. Systemic anticancer therapy within 28 days prior to registration. In absence of persisting toxicity, 5 half-lives since completion of prior anti-cancer therapy is acceptable.
3. Therapeutic or experimental monoclonal antibodies within 60 days prior to registration.
4. Systemic corticosteroid therapy or any other form of immunosuppressive therapy within 14 days prior to registration. Patients that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections will not be excluded from the study.
5. Major surgery within 28 days prior to registration.
6. Radiation therapy within 14 days prior to of registration.
7. History of, or active ethanol abuse or hepatitis (eg, alcohol or non-alcohol steatohepatitis [NASH], drug related, auto immune, virally related).
8. Live vaccine within 30 days prior to registration.
9. Active and clinically significant bacterial, fungal or viral infection including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness (HIV testing is not required), including patients who have an active infection requiring systemic therapy. Active herpes simplex or herpes zoster. Patients on prophylaxis for herpes infection who started taking medication at least 30 days prior to study entry, and have no active signs of active infection, and whose last active infection was more than 6 months prior to registration, may enter the study, and should continue to take the prescribed medication for the duration of the study.
10. Known prior or suspected hypersensitivity to study drugs or any component in their formulations (including patients who are known to be positive for anti-drug antibodies (ADA) to mogamulizumab or PF-05082566).
11. Patients who previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody.
12. Patients with a history of autoimmune disease (eg, rheumatoid arthritis, Addison's syndrome, multiple sclerosis, uveitis, systemic lupus erythematosus or Wegener's granulomatosis). Patients with vitiligo or alopecia are eligible. Patients with Graves disease or psoriasis not requiring systemic treatment within the past 3 years are eligible. Patients with hypothyroidism with stable hormone replacement are eligible.
13. Patients with known inflammatory bowel disease eg, ulcerative colitis, Crohn's disease, or celiac disease.
14. Hypertension that cannot be controlled by medications (>150/100 mmHg despite optimal medical therapy).
15. Any of the following within the 12 months prior to registration: myocardial infarction, congenital long QT syndrome, torsade de points, arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), right bundle branch block and left anterior hemiblock (bifascicular block), unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (CHF New York Heart Association class III or IV), cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism, ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, atrial fibrillation of any grade, or QTcF interval >470 msec at screening.
16. Diagnosis of any other malignancy within 2 years prior to registration.
17. Pregnant female patients; breastfeeding female patients; male patients with partners currently pregnant; male and female patients of childbearing potential who are unwilling or unable to use two (2) highly effective methods of contraception as outlined in this protocol for the duration of the study and for 60 days after last dose of investigational product.
18. Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
19. Participation in other therapeutic studies within 4 weeks before the current study begins and/or during study participation.
20. Patients who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer or KHK employees directly involved in the conduct of the study.