| 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)] triple-negative breast cancer (TNBC), or colorectal cancer (CRC)]. |
|
| 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, breast cancer and colorectal cancer. |
|
| 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 | 19.0 |
| 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 a single dose level of avelumab in
combination with increasing dose levels of other immune modulators in patients with
locally advanced or metastatic solid tumors in order to select the RP2D(s)/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 solid tumors. |
|
| 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 PK 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 solid tumors;
To assess the correlation of antitumor activity of avelumab and other immune modulators with immune biomarkers in baseline tumor tissue. |
|
| 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
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. For Phase 2 and additional patients enrolled beyond the first 3 in a Phase 1b cohort: 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. HPV status based on locally approved testing for patients with SCCHN, and MSI status based on locally approved testing for patients with CRC.
Patients with a history of PD-1 or PD-L1 inhibitor refractory disease (best response of PD) are not eligible.
Combo A- 1b: NSCLC that has progressed on standard therapy or for which no standard therapy is available.
Phase 2:
NSCLC, melanoma, or SCCHN in any line of therapy;
NSCLC patients with tumor ALK translocations or EGFR mutations must have received, or been refractory/intolerant to, standard therapy.
TNBC that has progressed after 1 line of therapy or is ineligible for/intolerant to SOC; or
SCLC that has progressed after at least 1 line of platinum-containing therapy or is ineligible for/intolerant to SOC.
NSCLC first-line Stage IV or recurrent NSCLC that is histologically proven. Patients must not have received treatment for their metastatic or recurrent disease. Neither activating EGFR mutation nor ALK 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.
Combo B- 1b:
NSCLC, melanoma, or SCCHN that has progressed after at least 1 line of standard therapy or is ineligible for/intolerant to SOC.
Phase 2:
NSCLC, melanoma, SCCHN, or microsatellite instability-high (MSIhigh) CRC in any line of therapy; or
MSS CRC that has progressed after at least 2 lines of standard therapy or is ineligible for/intolerant to SOC.
NSCLC patients with tumor ALK translocations or EGFR mutations must have received, or been refractory/intolerant to, standard therapy.
Combo C- 1b:
Ovarian cancer, SCCHN, NSCLC, or gastric cancer, that has progressed after at least 1 line of standard therapy or is ineligible for/intolerant to SOC.
MSIhigh CRC in any line of therapy;
Phase 2 (up to 2 of the following tumor types will communicated by PACL):
NSCLC, SCCHN, or MSIhigh CRC in any line of therapy;
Ovarian cancer or gastric cancer that has progressed after at least 1 line of therapy or is ineligible for/intolerant to SOC; or
MSS CRC that has progressed after at least 2 lines of standard therapy or is ineligible for/intolerant to SOC.
NSCLC patients with tumor ALK translocations or EGFR mutations must have received or been refractory/intolerant to standard therapy.
Combo D-1b:
NSCLC, melanoma, or SCCHN that has progressed after at least 1 line of standard therapy or is ineligible for/intolerant to SOC;
MSIhigh CRC in any line of therapy;
Bladder cancer that has progressed after at least 1 line of standard therapy or is ineligible for/intolerant to SOC.
Phase 2 (up to 2 of the following tumor types will communicated by PACL):
NSCLC, melanoma, SCCHN, or MSIhigh CRC in any line of therapy;
MSS CRC that has progressed after at least 2 lines of standard therapy or is ineligible for/intolerant to SOC; or
Inoperable or metastatic transitional cell carcinoma of the bladder that has progressed after at least 1 line of standard therapy or is ineligible for/intolerant to SOC. Other urothelial tumor types may be considered upon consultation with the Sponsor.
NSCLC patients with tumor ALK translocations or EGFR mutations must have received or been refractory/intolerant to standard therapy.
2. Age ≥18 years (≥20 years where applicable according to local regulation).
3. ECOG Performance Status (PS) 0 or 1.
4. Est. life expectancy of at least 3 months.
5. Adequate bone marrow function (defined in protocol)
6. Adequate renal function, with estimated creatinine clearance ≥50 mL/min
(Phase 1b) or ≥30 mL/min (Phase 2) as calculated using the Cockcroft-Gault (CG) equation.
7. Adequate liver function:
a. Total serum bilirubin ≤1.5 x ULN unless the patient has documented Gilbert syndrome;
b. AST and ALT ≤2.5 x ULN, or ≤5 x ULN if there is documented metastatic disease to the liver.
8. Resolved acute effects of any prior therapy to baseline severity or NCI CTCAE v4.03 Grade ≤1 (except alopecia and Grade ≤2 sensory neuropathy are acceptable).
|
|
| E.4 | Principal exclusion criteria |
Patients with any of the following characteristics/conditions will not be included in the study:
1. Monoclonal antibody based anti-cancer therapy within 28 days prior to study entry or small-molecule based anti-cancer therapy (targeted therapy or chemotherapy) within 14 days prior to study entry.
2. Current use of immunosuppressive medication at time of randomization. Please refer to the protcol for exceptions to this criteria.
3. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Please refer to the protcol for exceptions to this criteria.
4. Known prior or suspected hypersensitivity to investigational products or any component in their formulations, including known severe hypersensitivity reactions to mAbs (NCI CTCAE v4.03 Grade ≥3).
5. Major surgery within 4 weeks or radiation therapy within 14 days prior to study entry. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has been completed 48 hours prior to study entry and there is at least 1 measurable lesion that has not been irradiated.
6. Patients with known symptomatic brain metastases requiring steroids. 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 study entry, have discontinued corticosteroid treatment for these metastases for at least 4 weeks prior to study entry, and are neurologically stable.
7. Previous high-dose chemotherapy requiring stem cell rescue.
8. Prior allogeneic stem cell transplant or organ graft.
9. 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 Class ≥II), or serious cardiac arrhythmia requiring medication.
10. 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. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening tests positive).
16. Vaccination within 4 weeks of the first dose of investigational product and while on trial is prohibited except for administration of inactivated vaccines (for example, inactivated influenza vaccines).
17. Diagnosis of any other malignancy within 2 years prior to study entry, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix, or low-grade (Gleason ≤6) prostate cancer on surveillance with no plans for treatment intervention (eg, surgery, radiation or castration).
18. 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.
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 NCI CTCAE v4.03 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 conditions, psychiatric conditions 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 products 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.
22. Pregnant female patients; breastfeeding female patients; male patients with partners currently pregnant; male patients able to father children and female patients of childbearing potential who are unwilling or unable to use 2 highly effective method(s) of contraception as outlined in this protocol for the duration of the study and for at least 90 days after the last dose of investigational product or longer as required by local regulations.
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|
| 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 2: 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 | 29 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 1 |
| 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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