| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced malignances in the first-line treatment |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10048683 |
| E.1.2 | Term | Advanced cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• Phase 1b lead-in: To assess Dose-Limiting Toxicity (DLT) rate of avelumab in combination with chemotherapy, as first-line treatment in patients with locally advanced or metastatic solid tumors.
•To assess, per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, the Objective Response Rate (ORR) of avelumab in combination with chemotherapy, as first-line treatment in patients with locally advanced or metastatic solid tumors. |
|
| E.2.2 | Secondary objectives of the trial |
•To assess the overall safety and tolerability of avelumab in combination with chemotherapy;
•To characterize the PK of avelumab and chemotherapy when given in combination;
•To evaluate the immunogenicity of avelumab, when given in combination with chemotherapy;
•To assess the antitumor activity, per RECIST v1.1,of avelumab in combination with chemotherapy;
•To assess the correlation of antitumor activity, per RECIST v1.1, of avelumab in combination with chemotherapy, with mutational load in baseline tumor tissue;
•To assess the correlation of Programmed Death-Ligand 1 (PD-L1) expression in baseline tissue and changes in this marker on-treatment, with antitumor activity, per RECIST v1.1, of avelumab in combination with chemotherapy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid
tumor that is not amenable for treatment with curative intent as follows:
For all groups:
- Measurable disease by RECIST v1.1 with at least 1 measurable lesion;
- No prior systemic treatment for unresectable locally advanced or metastatic disease for the tumor type under study. If prior systemic chemotherapy treatment was given in the adjuvant or neo-adjuvant setting or as part of radiotherapy-chemotherapy treatment, disease free interval after stop of systemic treatment must be more than 6 months for non-squamous NSCLC and more than 12 months for UC;
- Availability of tumor specimens: A mandatory archived formalin-fixed, paraffin-embedded (FFPE) tumor tissue block sufficient in size to allow for sectioning of at least 10 slides must be available from the most recent primary or metastatic tumor biopsy or resection prior to start of study therapy. The archived sample must have been taken within 18 months prior to enrollment, with no intervening systemic anti-cancer therapy. If such an archived sample is not available, a de novo (ie, fresh) tumor sample must be obtained prior to enrollment. If blocks cannot be provided, then at least 10, but preferably 15, freshly prepared slides must be provided. Core needle or excision biopsies are required. If a patient has only one measurable (target) lesion and no suitable archived tumor tissue to serve as a baseline sample, then that one measurable (target) lesion should not be biopsied and that patient is not eligible for enrollment.
For Group A:
- Non-squamous NSCLC, with no activating EGFR mutations, ALK or ROS1 translocations/rearrangements. If monotherapy pembrolizumab is available as a standard of care treatment option, patients must have a tumor proportion score (TPS) <50% for PD-L1 (via the 22C3 pharmDx or the Ventana (SP263) PD-L1 IHC assay).
- Transitional cell carcinoma of the urothelium including the bladder, urethra, renal pelvis, and ureter.
2. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
3. Age ≥18 years (≥20 years in Japan).
4. Estimated life expectancy of at least 90 days.
5. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × ULN, an AST level ≤ 2.5 × ULN, and an ALT level ≤ 2.5 × ULN.
6. Adequate renal function defined by an estimated creatinine clearance ≥ 50 mL/min according to the Cockcroft-Gault formula or by 24 hour urine collection for creatinine clearance or according to local institutional standard method.
7. Adequate bone marrow function including: ANC ≥1,500/mm³ or ≥1.5 × 10 9 / L; platelets ≥ 100,000/mm³ or ≥100 × 10 9 / L; hemoglobin ≥ 9 g/dL (may have been transfused)
8. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
9. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
10. Pregnancy test (for females of childbearing potential) negative at screening. Female patients of non-childbearing potential must meet at least 1 of the following criteria:
a. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy and/or bilateral salpingectomy;
c. Have medically confirmed ovarian failure. |
|
| E.4 | Principal exclusion criteria |
1. Prior immunotherapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40, anti-glucocorticoid induced tumor necrosis factor (TNF) receptor (GITR), anti-lymphocyte activation gene-3 (LAG-3), anti-T cell immunoglobulin and mucin (TIM-3) domain, or anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibody (including ipilimumab), IDO1 inhibitor, or any other antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways
2. Patients with known symptomatic central nervous system (CNS) metastases requiring steroids. Patients with previously diagnosed CNS metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to enrollment, have discontinued corticosteroid treatment for these metastases for at least 14 days, and are neurologically stable
3. Diagnosis of any other malignancy within 2 years prior to enrollment. Adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the bladder, breast, or cervix, or low grade (Gleason ≤6) prostate cancer on surveillance without any plans for treatment intervention (eg, surgery, radiation, or castration) are allowed
4. Current use of immunosuppressive medication at the time of enrollment, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection; b. systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or equivalent; c. steroids as premedication for hypersensitivity reactions
5. Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent
6. Prior organ transplantation including allogenic stem-cell transplantation
7. Active infection requiring systemic therapy
8. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome
9. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
10. Vaccination within 4 weeks of the first dose of investigational product is prohibited except for administration of inactivated vaccines
11. Known prior severe hypersensitivity to the investigational products or any component in their formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥3)
12. Known prior severe hypersensitivity to platinum-related compounds for all cohorts, to pemetrexed for patients enrolled in Cohorts A1/A3, and to gemcitabine for patients enrolled in Cohort A2/A4 (NCI CTCAE v4.03 Grade ≥3)
13. Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade > 1); however alopecia, sensory neuropathy Grade ≤2, or other Grade ≤2 AEs not constituting a safety risk based on Investigator's judgment are acceptable
14. Known history of colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis
15. Ongoing cardiac dysrhythmias of NCI CTCAE v4.03 Grade ≥ 2 or prolongation of the QTcF interval to >480 msec
16. Clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke (<6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication
17. Major surgery ≤28 days or major radiation therapy ≤14 days prior to enrollment. Prior palliative radiotherapy (≤10 fractions) to metastatic lesion(s) is permitted, provided it has been completed at least 48 hours prior to enrollment
18. Participation in other studies involving investigational drug(s) within 28 days prior to study entry
19. Concurrent treatment with a prohibited medication listed in protocol
20. Other 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
21. Investigator 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, including their family members, directly involved in the conduct of the study
22. Pregnant female patients; breastfeeding female patients; fertile male patients and female patients of childbearing potential who are unwilling or unable to use at least 1 highly effective methods of contraception as outlined in this protocol for the duration of the study and for at least 90 days after the last dose of chemotherapy (for male and female) or at least 30 days after the last dose of avelumab (for female), whichever is longer |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Phase 1b lead-in: First 2 cycles DLT.
• Confirmed Objective Response, as assessed by the Investigator using RECIST v1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• AEs as characterized by type, severity (as graded by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.03), timing, seriousness, and relationship to study treatments;
• Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE v.4.03) and timing;
• PK parameters of avelumab;
• PK parameters of chemotherapies, as data permit;
• Anti-Drug Antibody (ADA) levels;
• Time-to-event endpoints including PFS, duration of response (DR), and time to tumor response (TTR), as assessed by the Investigator using RECIST v1.1; and Overall Survival (OS);
• Mutational load within baseline tumor tissue;
• PD-L1 expression in baseline and on-treatment tumor tissue. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Baseline up to approximately 24 months |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| safety and efficacy of avelumab in combination with chemotherapy |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Czech Republic |
| Hungary |
| Italy |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last Subject Last Visit (LSLV) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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