GESELECTEERDE LOKAAL GEVORDERDE OF GEMETASTASEERDE CARCINOMEN SELECTED LOCALLY ADVANCED OR METASTATIC CANCERS
Conditions
Interventions
Part A Monotherapy:
The dose of PF-04518600 will be administered intravenously (through a vein)
over a 60 minute period once every 2 weeks. If the drug is safely tolerated (no
unsafe or unacceptable
cancer
phase 1
Sponsors
Pfizer
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: Part A Monotherapy 1. Part A1 only: Patients with histological or cytological diagnosis of HNSCC, HCC, melanoma, or clear cell RCC who progressed on or are intolerant to standard therapy, for which no standard therapy is available or who decline standard therapy. 2. Part A2 only: Patients with histological or cytological diagnosis of advanced/metastatic HCC who are treatment naïve and have declined standard of care, or have had at least 1 prior line of systemic therapy. Prior anti-PD-L1/PD-1 therapy is allowed. 3. Patients must have at least one measurable lesion as defined by RECIST version 1.1, be willing to undergo the mandatory biopsies and there is no excessive risk from biopsy as judged by the Investigator. 4. Adults (men and women) age *18 years (for Japan only: *20 years of age). 5. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1. 6. Adequate Bone Marrow Function, including: * ANC * 1,500/mm3 or *1.5 x 109/L. * Platelets *100,000/mm3 or *100 x 109/L. * Platelets for HCC only: * 60,000/mm3. * 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. 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. 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. 8. 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; *5.0 x ULN if there is liver involvement secondary to tumor. 9. Inclusion for HCC patients only: - Child-Pugh Class A or B with a score of 7 (see Appendix 3) 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. - International Normalized Ratio (INR) * 2.3 or Prothrombin Time (PT) * 6 seconds above control. 10. Resolved acute effects of 10. Resolved acute effects of any prior therapy to baseline severity or Grade *1 CTCAE except for AEs not constituting a safety risk by investigator judgment. 11. 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). 12. 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 laboratory*s reference range for postmenopausal women. 13. Evidence of a personally signed and
Exclusion criteria
Exclusion criteria: Part A Monotherapy 1. 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. 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. 3. 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. 4. Bleeding esophageal or gastric varices <2 months prior to informed consent document (ICD) date. 5. Unmanageable ascites (limited medical treatment to control ascites is permitted, but all patients with ascites will require review by sponsor*s medical monitor). 6. Major surgery within 4 weeks of starting study treatment. 7. Patients who have undergone solid organ or hematopoietic transplant. 8. 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. 9. 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. 10. Previous high dose chemotherapy requiring stem cell rescue. 11. Prior treatment with an OX40 agonist. 12. Currently require doses of systemic immune suppressive medication [eg, (* 10 mg of prednisone or equivalent ((*1.5 mg of dexamethasone)]. 13. 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. 14. 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). 15. Patients with a previous history of anthracycline treatment and are at risk of cardiac failure
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Endpoints for Part A1 Monotherapy Dose Escalation Primary Endpoints: * Dose limiting toxicities (DLTs) observed in each patient during the first 98 days in order to determine the MTD. * Adverse Events (AEs) as characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE ) v 4.03, timing, seriousness and relationship to study therapy PF 04518600. * Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v. 4.03) and timing. Endpoints for Part A2 Monotherapy Dose Expansion Primary Endpoints: * AEs as characterized by type, frequency, severity (as graded by NCI CTCAE v 4.03), timing, seriousness and relationship to study therapy PF 04518600. * Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v. 4.03) and timing. Endpoints for Part B1 Combination Therapy Dose Escalation Primary Endpoints: * DLTs observed in each patient during the first 98 days in order to determine the MTD. * AEs as characterized by type, frequency, severity (as graded by NCI CTCAE v 4.03), timing, seriousness and relationship to PF 04518600/ PF-05082566 combination. * Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v. 4.03) and timing. Endpoints for Part B2 Combination Therapy Dose Expansion Primary Endpoints: * AEs as characterized by type, frequency, severity (as graded by NCI CTCAE v 4.03), timing, seriousness and relationship to PF 04518600/ PF-05082566 combination. * Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v. 4.03) and timing. | — |
Secondary
| Measure | Time frame |
|---|---|
| Endpoints for Part A1 Monotherapy Dose Escalation Secondary Endpoints: * Objective tumor response, as assessed using the RECIST version 1.1 and irRECIST. * Anti-tumor activity assessments of: PFS, TTP, SD, DR by RECIST version 1.1 and irRECIST and OS * Overall survival rates at 6 months, 1 year and 2 years. * Pharmacokinetic parameters of PF 04518600: SDo-Cmax, AUCsdo, AUCinf, t1/2, as data permit. MD (assuming steady state is achieved) - Css,max, AUCss, t1/2, Css,min, Css,av, CL, and Vss, and Rac (AUCss,/AUCsdo,) as data permit. * Incidence of anti-drug antibody (ADA) and NAb against PF 04518600. * Levels of free OX40 receptor expressed on T cells in peripheral blood. Endpoints for Part A2 Monotherapy Dose Expansion Secondary Endpoints: * Objective tumor response, as assessed using the RECIST version 1.1 and irRECIST. * Anti-tumor activity assessments of: PFS, TTP, SD, DR by RECIST version 1.1 and irRECIST and OS. * Overall survival rates at 6 months, 1 year and 2 years. * Pharmacokinetic parameters of PF 04518600: SDo-Cmax, AUCsdo,, AUCinf, t1/2, as data permit. MD (assuming steady state is achieved)-Css,max, AUCss,, t1/2, Css,min, Css,av, CL, and Vss, and Rac (AUCss,/AUCsdo,) as data permit. * Incidence of ADA and NAb against PF 04518600. Endpoints for Part B1 Combination Therapy Dose Escalation Secondary Endpoints: * Objective tumor response, as assessed using the RECIST version 1.1 and irRECIST. * Anti-tumor activity assessments of: PFS, TTP, SD, DR by RECIST version 1.1 and irRECIST and OS. * Overall survival rates at 6 months, 1 year and 2 years. * Pharmacokinetic parameters of PF 04518600 and utomilumab: SDo-Cmax, AUCsdo,, AUCinf, t1/2, as data permit. MD (assuming steady state is achieved)-Css,max, AUCss,, t1/2, Css,min, Css,av, CL, and Vss, and Rac (AUCss, /AUCsdo,) as data permit. * Incidence of ADA and NAb against PF 04518600 and utomilumab. Endpoints for Part B2 Combination Therapy Dose Expansion Secondary Endpoints | — |
Countries
France, Japan, Netherlands, United States of America
Outcome results
None listed