| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced or metastatic solid tumors [eg, non-small cell lung cancer (NSCLC), melanoma, and squamous cell carcinoma of the head and neck (SCCHN)]. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced cancers including non-small cell lung cancer, melanoma, and squamous cell carcinoma of the head and neck. |
|
| 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 | 20.0 |
| 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 safety and tolerability of avelumab in combination with increasing dose levels of other immune modulators in combination with a single dose level of avelumab in patients with advanced solid tumors in order to select the Recommended Phase 2 Dose(s) (RP2D)/schedule for the combination.
Phase 2: To assess objective response (OR) of avelumab in combination with other immune modulators in patients with locally advanced or metastatic cancer [ie, non-small cell lung cancer (NSCLC), melanoma, or squamous cell carcinoma of the head and neck
(SCCHN)]. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the overall safety and tolerability of avelumab and other immune modulators when given in combination;
To characterize the pharmacokinetics of avelumab and other immune modulators when given in combination;
To evaluate the immunogenicity of avelumab and other immune modulators when given in combination;
To assess the antitumor activity of avelumab and other immune modulators when given in combination in patients with locally advanced or metastatic NSCLC, melanoma, and/or SCCHN;
To evaluate candidate predictive biomarkers of sensitivity or resistance to avelumab in combination with other immune modulators in pre-treatment tumor tissue that may aid in the identification of patient subpopulations most likely to benefit from treatment; |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histological or cytological diagnosis of advanced/metastatic solid tumor as follows
For all combinations:
Measurable disease by RECIST v1.1 with at least 1 measurable lesion that has not previously been irradiated.
Availability of tumor specimens: For Phase 1b: Archival formalin-fixed paraffin-embedded (FFPE) tissue is required if available for the first 3 patients enrolled in a cohort, including replacement patients. For additional patients enrolled in each Phase 1b cohort and Phase 2, FFPE tissue must be available from the most recent primary or metastatic tumor biopsy or resection prior to start of study therapy, taken within 1 year prior to study entry, with no intervening systemic anti-cancer therapy. De novo, excision, fine needle biopsies may be used
The following baseline data should be available for each respective tumor type: human papilloma virus (HPV) status based on locally approved testing for patients with SCCHN, EGFR, ALK and ROS-1 status for non-squamous NSCLC and PD-L1 status based on locally approved testing for first-line NSCLC patients.
Unless specified, the prior therapy requirements apply to anti-cancer drug treatment in advanced stage/metastatic disease. If patient relapses within 1 year of adjuvant/neoadjuvant treatment, the respective therapy must be counted as treatment in advanced disease/metastatic setting.
Combination A
Phase 1b: NSCLC that has progressed on standard therapy or for which no standard therapy is available.
Phase 2:
A1 – A5: NSCLC, melanoma, or SCCHN in any line of therapy; NSCLC patients with tumor anaplastic lymphoma kinase (ALK) translocations or epidermal growth factor receptor (EGFR) mutations must have received, or been refractory/intolerant to standard therapy.
A6: TNBC that has progressed after 1 line of therapy or is ineligible for/intolerant to SOC; or
A7: SCLC that has progressed after up to 1 line of prior therapy in advanced metastatic setting or is ineligible for/intolerant to standard of care (SOC). No prior PD-1/PD-L1 therapy allowed.
A8, A9, and A10: NSCLC first-line Stage IV or recurrent NSCLC that is histologically proven and is demonstrated to express PD-L1. Patients must not have received treatment for their metastatic or recurrent disease. Neither activating EGFR mutation nor ALK or ROS1 translocation/rearrangement are permitted (non-squamous cell
histologies require testing if status is unknown).
Patients could have received adjuvant chemotherapy or locoregional treatment that included chemotherapy for locally advanced disease as long as disease treatment occurred at least 6 months prior to study entry. No prior PD-1/PD-L1 therapy allowed.
Combination B
Phase 1b:NSCLC, melanoma, or SCCHN that has progressed after at least 1 line of standard therapy or is ineligible for/intolerant to SOC; No prior PD-1/PD-L1 therapy allowed.
Phase 2:NSCLC, Cutaneous or mucosal metastatic melanoma, SCCHN: Up to 2 lines of prior therapy in advanced/metastatic disease settings allowed. No prior PD-1/PD-L1 therapy allowed.
Combination C
Phase 1b:
NSCLC, SCCHN: Up to 2 lines of prior therapy in advanced/metastatic disease settings allowed. Gastric cancer that has progressed after at least 1 line or is ineligible for/intolerant to SOC and not more than 2 lines of standard therapy in advanced/metastatic disease settings or is ineligible for/intolerant to SOC.
Platinum resistant ovarian cancer that has not received more than 2 lines of standard therapy in the platinum resistant setting or is ineligible for/intolerant to SOC.
TGCT/PVNS that is either inoperable or requires extensive surgery for resection. Prior treatment with agents targeting CSF-1 or CSF-1R is not allowed.
No prior PD-1/PD-L1 therapy allowed
Phase 2: Up to 2 of the tumor types included in Phase 1b will be selected and communicated to the sites by PACL
Combination D
Phase 1b: NSCLC, Cutaneous or mucosal metastatic melanoma, SCCHN, Bladder cancer: Up to 2 lines of prior therapy in advanced/metastatic disease settings allowed. No prior PD-1/PD-L1 therapy allowed. Phase 2:
Up to 2 of the tumor types included in Phase 1b will be selected and communicated to the sites by PACL.
Combination E
Phase 1b: NSCLC, Cutaneous or mucosal metastatic melanoma, Bladder cancer, Renal cell carcinoma: Up to 2 lines of prior therapy in advanced/metastatic disease settings allowed. No prior PD-1/PD-L1 therapy allowed. Platinum resistant ovarian cancer that has not received more than 2 lines of standard therapy in the platinum resistant setting or is ineligible for/intolerant to SOC. No prior PD-1/PD-L1 therapy allowed.
Phase 2: Up to 3 of the tumor types included in Phase 1b will be selected and communicated to the sites by PACL
2. Age ≥18 years
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
4. Estimated life expectancy of at least 3 months |
|
| E.4 | Principal exclusion criteria |
1. Systemic chemotherapy within 28 days prior to study entry
2. Current or prior use of immunosuppressive medication within 7 days prior to study entry
3. Active autoimmune disease requiring systemic steroids or immunosuppressive agents within 7 days prior to study entry
4. Known prior or suspected hypersensitivity to investigational products, including known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3), and any history of anaphylaxis or uncontrolled asthma
5. Major surgery within 4 weeks or radiation therapy within 14 days prior to study entry
6. Patients with known symptomatic brain metastases requiring steroids
7. Previous high-dose chemotherapy requiring stem cell rescue
8. Prior allogeneic stem cell transplant or organ graft
9. Any of the following within 6 months prior to study entry: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack
10. Deep vein thrombosis or symptomatic pulmonary embolism within 6 months prior to study entry
11. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) related illness
12. Existing periorbital edema
13. Hypocalcemia (serum albumin adjusted calcium <7.5 mg/dL), clinically significant bone disease that may affect safe study participation at the discretion of the investigator, or recent bone fracture (within 12 weeks prior to study entry).
14. Active infection requiring systemic therapy
15. Positive HBV or HCV test indicating acute or chronic infection
16. Administration of a live vaccine within 4 weeks prior to study entry
17. Diagnosis of other malignancy within 5 years, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or cervix, or low-grade (Gleason ≤6) prostate cancer
18. Patients who are 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
19. Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry and/or during study participation
20. Persisting toxicity related to prior therapy >Grade 1 (alopecia and Grade ≤2 sensory neuropathy, or other Grade ≤2 AEs not constituting a safety risk based on Investigator judgment are acceptable); previous Grade ≥3 irAE within 3 months prior to study entry; or unresolved irAEs prior to study entry.
21. Other severe acute or chronic medical condition, including colitis, inflammatory bowel disease, and pneumonitis or psychiatric condition, recent or active suicidal ideation or behavior, or end stage renal disease on hemodialysis, or laboratory abnormality that may increase the risk associated with study participation or investigational products administration or may interfere with the interpretation of results and, in the judgment of the Investigator, would make the patient inappropriate study entry
22. Male and female patients able to have children who are unwilling or unable to use 2 highly effective method(s) of contraception for the duration of the study and for at least 90 days after the last dose of investigational product
23. Combination E only: Current use or anticipated need for food or drugs that are known strong CYP1A2 inhibitors, including their administration within 10 days prior to the first PF-06840003 dose
24. Combination E only: Patients with active seizure disorder (requiring continued anti-seizure treatment).
25. Combination E only: Prolonged QTc at baseline (>480 ms). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b Lead-in: First 2 Cycles Dose Limiting Toxicity (DLT).
Phase 2: Confirmed objective response (OR), as assessed by the investigator using RECIST v1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1b: First 8 weeks of treatment
Phase 1: Baseline up to approximately 24 month |
|
| E.5.2 | Secondary end point(s) |
1. 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;
2. Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE
v.4.03) and timing;
3. PK parameters (Cmax and Ctrough);
4. ADA levels;
5. Time-to-event endpoints including Time to Tumor Response (TTR), duration of response (DR), progression-free survival (PFS) as assessed by the investigator using RECIST v1.1, and overall survival (OS);
6. Confirmed OR during Phase 1b, as assessed by the investigator using RECIST v1.1;
7. Biomarkers such as PD-L1 expression and tumor infiltrating CD8+ lymphocytes in
baseline tumor tissue. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Adverse events should be documented and recorded at each visit using NCI CTCAE version 4.03.
2. On treatment, labs to be performed prior to dosing with study treatments unless otherwise indicated
3. PK/immunogenicity blood sampling will be collected as described in the Schedule of
Activities for each combination.
4. Anti-tumor activity will be assessed at 8-week intervals, and repeated at least 4 weeks after initial documentation. After 1 year from randomization or first dose ( tumor assessments will be conducted at 12-week intervals.
5. Confirmed OR at Phase 1b: First 8 weeks of treatment
7. Biomarkers -Baseline, End of Treatment/Withdrawal |
|
| 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 | Yes |
| 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 | Yes |
| 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 |
|
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 37 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
| France |
| Germany |
| Japan |
| Netherlands |
| 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
|
End of trial in a Member State of the European Union (EU) is defined as the time at which it is deemed that a sufficient number of patients have been recruited and completed the study as stated in the regulatory application (ie, clinical trial application (CTA)) and ethics application in the Member State.
End of Trial in all other participating countries is defined as Last Subject Last Visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 12 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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