A PHASE 1, OPEN-LABEL, DOSE ESCALATION STUDY OF PF-04518600 AS A SINGLE AGENT AND IN COMBINATION WITH PF-05082566 IN PATIENTS WITH SELECTED LOCALLY ADVANCED OR METASTATIC CARCINOMAS
The goal of this clinical research study is to learn about the effects of the study drugs, PF-04518600 and PF-05082566, and to find out what side effects occur when PF-04518600 is given alone or in combination with PF-05082566. Researchers also want to learn: how long the study drug(s) stay in the body, if the body makes antibodies (substances that are created by the immune system and may attack foreign cells or substances) against the study drug, if the study drug(s) affect your immune system, and if the study drug(s) can help to control the disease. PF-04518600 and PF-05082566 are types of molecules called monoclonal antibodies (mAb). These particular monoclonal antibodies are designed to trigger the immune system to attack tumor cells.
Disease Group: Gastrointestinal,Genitourinary,Head And Neck,Melanoma
Treatment Agent: PF-04518600,PF-05082566
Treatment Location: Both at MDACC & and Other Sites
Objectives for Part A Monotherapy
IRB Review and Approval Date: 08/21/2015
Recruitment Status: Open
Projected Accrual: 190
1) Part A Monotherapy (Part A1 only): Patients with histological or
cytological diagnosis of HNSCC, HCC, melanoma, or RCC who progressed on
or are intolerant to standard therapy, for which no standard therapy is
available or who decline standard therapy.
2) Part A Monotherapy (Part A2 only): Patients with histological or cytological diagnosis of melanoma and HCC patients who progressed on or are intolerant to standard therapy, for which no standard therapy is available or who decline standard therapy.
3) Part B Combination Therapy (Part B1 only): Patients with histological or cytological diagnosis of NSCLC, HNSCC, melanoma, urothelial bladder carcinoma (including renal pelvis, ureters, urinary ladder, and urethra), gastric or squamous cell carcinoma of the uterine cervix who progressed on or are intolerant to standard therapy, for which no standard therapy is available, or who decline standard therapy.
4) Part B Combination Therapy (Part B2 Arm 1 only): Patients with histological or cytological diagnosis of HNSCC who progressed on or are intolerant to standard therapy, for which no standard therapy is available, or the patient must have declined standard therapy. HNSCC patients must NOT have previously received prior anti-PD-L1 or anti-PD-1 mAb.
5) Part B Combination Therapy (Part B2 Arm 2 only): Histological or cytological diagnosis of NSCLC who progressed on or are intolerant to standard therapy, for which no standard therapy is available, or the patient must have declined standard therapy. Patients must have A) previously received prior anti-PD-L1 or anti-PD-1 mAb as most recent therapy, AND B) did not have progressive disease as best overall response on recent PD-L1/PD-1 therapy, AND C) who subsequently progressed, or are intolerant to this therapy.
6) (Part A & Part B): Patients must have at least one measurable lesion as defined by RECIST version 1.1 and be willing to undergo the mandatory biopsies.
7) (Part A & Part B): Adults (men and women) age >/=18 years ( for Japan only : >/= 20 years of age)
8) (Part A & Part B): Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
9) (Part A & Part B): Adequate Bone Marrow Function, including: ANC >/=1,500/mm^3 or >/=1.5 x 10^9/L. Platelets >/=100,000/mm^3 or >/=100 x 10^9/L. (Part A only) Platelets for HCC only: >/=60,000/mm^3. Hemoglobin >/=9 g/dL. Limited transfusions to reach this value are allowed, after discussion with sponsor’s medical monitor. There should not be a chronic need for transfusions in the recent (approximately 3 month) past.
10) (Part A & Part B): 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. If an estimated creatinine clearance is believed to be inaccurate for a patient, 24 hr urine collection with actual assessment of creatinine clearance is allowed.
11) (Part A & Part B): Adequate Liver Function (all patients, except HCC, see Inclusion Criteria 9), including: Total serum bilirubin </=1.5 x ULN unless the patient has documented Gilbert syndrome. Aspartate and alanine aminotransferase (AST & ALT) </=2.5 x ULN; (Part A only) </=5.0 x ULN if there is liver involvement secondary to tumor.
12) (Part A only): Inclusion for HCC patients only: Child-Pugh Class A or B with a score of 7 and no prior history of hepatic encephalopathy. Serum bilirubin </=3 mg/dL. Serum Albumin >/=2.8 g/dL. AST and ALT </=5.0 x ULN. Amylase and lipase <1.5 ULN. International Normalized Ratio (INR) </=2.3 or Prothrombin Time (PT) </=6 seconds above control.
13) (Part A & Part B): Resolved acute effects of any prior therapy to baseline severity or Grade </=T1 CTCAE except for AEs not constituting a safety risk by investigator judgment.
14) (Part A & Part B): Serum or urine pregnancy test (for women of childbearing potential) negative at screening and at the baseline visit before the patient may receive the investigational product).
15) (Part A & Part B): Male and female patients of childbearing potential and at risk for pregnancy must agree to use two highly effective method(s) of contraception throughout the study and for at least 90 days after the last dose of assigned treatment. Female patients who are not of childbearing potential as defined below, are eligible to be included (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 postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; a serum follicle stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal women.
16) (Part A & Part B): Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
17) (Part A & Part B): Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory tests and other procedures.
1) Part A Monotherapy (Part A only): Patients with known symptomatic
brain metastases requiring systemic corticosteroids. Patients with
previously diagnosed brain metastases are eligible if they have
completed their treatment and have recovered from the acute effects of
radiation therapy or surgery prior to the start of study medication,
have discontinued corticosteroid treatment for these metastases for at
least 4 weeks and are neurologically stable. Mild neurological deficits
are allowed, if they do not interfere with the ability to judge the
safety profile of PF-04518600.
2) Part B Combination Therapy (Part B only): Patients with known symptomatic brain metastases requiring systemic corticosteroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable. Mild neurological deficits are allowed, if they do not interfere with the ability to judge the safety profile of PF-04518600 / PF-05082566.
3) (Part A & Part B): History of or active autoimmune disorders (including but not limited to: Crohn’s Disease, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, Grave’s disease) and other conditions that compromise or impair the immune system.
4) (Part A & Part B): Active bacterial, fungal or viral infection including hepatitis B (HBV, see exception below for patients with HCC), hepatitis C (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) -related illness. For patients with HCC only: after the safety profile of a cohort has been established in 2-4 patients, and escalation to the next higher dose level has taken place, HCC patients enrolled into the expansion lower dose cohort meeting the following criteria can be enrolled: patients infected with the HBV or HCV but with minimal viral load (<20 IU/ml) at the moment of screening and who are being treated with either entecavir or tenofovir during the full study period.
5) (Part A & Part B): Bleeding esophageal or gastric varices <2 months prior to informed consent document (ICD) date.
6) (Part A & Part B): Unmanageable ascites (limited medical treatment to control ascites is permitted, but all patients with ascites will require review by sponsor’s medical monitor).
7) (Part A & Part B): Major surgery within 4 weeks of starting study treatment.
8) (Part A only): Patients who have undergone a liver transplant for HCC.
9) (Part A & Part B): Systemic anti-cancer therapy within 4 weeks of starting study treatment (6 weeks for mitomycin C or nitrosoureas). If systemic anti-cancer therapy was given within 4 weeks, patient may be included if 4-5 times elimination half-life of drug has passed.
10) (Part A & Part B): Radiation therapy within 4 weeks of starting study treatment, except: palliative radiotherapy to a limited field is allowed after consultation with sponsor’s medical monitor at any time during study participation, including during screening, unless it’s clearly indicative of disease progression.
11) (Part A & Part B): Previous high dose chemotherapy requiring stem cell rescue.
12) (Part A only): Prior treatment with an OX40 agonist.
13) (Part B only): Prior treatment with an OX40 agonist or a 4 - 1 BB agonist.
14) (Part A & Part B): Currently require doses of systemic immune suppressive medication [eg, >/=10 mg of prednisone or equivalent (>/=1.5 mg of dexamethasone)].
15) (Part A & Part B): History of Grade 3 or higher immune-mediated adverse event (including AST/ALT elevations that where considered drug related and cytokine release syndrome) that was considered related to prior immune-modulatory therapy (eg, checkpoint inhibitors, co-stimulatory agents etc.) or any grade immune-related AEs that required immune suppressive therapy.
16) (Part A & Part B): Patients with intolerance to or who have had a severe (>/=Grade 3) allergic or anaphylactic reaction to antibodies or infused therapeutic proteins, or patients who have had a severe allergic or anaphylactic reaction to any of the substances included in the investigational product (including excipients).
17) (Part A & Part B): Patients with a previous history of adriamycin treatment and are at risk of cardiac failure (New York Heart Association [NYHA] Class II or above.
18) (Part A & Part B): Any one of the following currently or in the previous 6 months: myocardial infarction, congenital long QT syndrome, torsade¡¦s de points, arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), 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 or other clinical significant episode of thrombo-embolic disease*. Ongoing cardiac dysrhythmias of NCI CTCAE grade >/=2, atrial fibrillation of any grade, or QTcF interval >470 msec at screening (except in case of right bundle branch block, these cases must be discussed with sponsor¡¦s medical monitor).
19) (Continuation from #18) *Cases must be discussed in detail with sponsor¡¦s medical monitor to judge eligibility.Anticoagulation (heparin only, no vitamin-K antagonists or factor Xa inhibitors) will be allowed if indicated.
20) (Part A & Part B): Participation in other interventional studies within 28 days before the current study begins and/or during study participation. Before joining Study B0601002, at least 28 days must have passed from last systemic study therapy administration. Participation in long term follow up is allowed if no procedures which may interfere with the interpretation of study results will be performed.
21) (Part A only): Patients in the 0.01 mg/kg cohort must not be </=50 kg in weight.
22) (Part B only): Patients that will receive 0.01 mg/kg PF-04518600 must not be </= 50 kg in weight.
23) (Part A & Part B): Pregnant female patients; breastfeeding female patients (including patients who are weaning their infants).
24) (Part A & Part B): 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 or sponsor¡¦s medical monitor, would make the patient inappropriate for entry into this study.
25) (Part A & Part B): 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 employees directly involved in the conduct of the study.
Information and next steps
Gastrointestinal,Genitourinary,Head And Neck,Melanoma
Melanoma Medical Oncology
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