| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced solid tumors who have relapsed or are refractory to anti-PD1 or anti-PDL1 therapy. |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
The primary objectives/endpoints of this trial are to:
-Assess the safety and tolerability profile of increasing doses of BI-1206, administered intravenously (IV) or subcutaneously (SC), in combination with pembrolizumab in subjects with advanced solid tumors.
- Identify dose-limiting toxicities (DLTs), determine the maximum tolerated dose (MTD) and select a recommended Phase 2 dose (RP2D) of BI-1206, given via IV infusion or SC injection in combination with pembrolizumab (administered at the standard dose of 200 mg every 3 weeks) to subjects with advanced solid tumors who are experiencing disease progression and have previously been treated with anti-PD1 or PDL1 antibodies.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives/endpoints of the trial are to:
-Study the PK profile of BI-1206 when administered IV or SC every 3 weeks in combination with pembrolizumab in subjects with advanced solid tumors.
-Assess the immunogenicity of BI-1206, administered IV or SC, in subjects with advanced solid tumors, when given in combination with pembrolizumab.
- Evaluate the effect of BI-1206 administered IV or SC in combination with pembrolizumab on CD32b receptor occupancy on B cells in subjects with advanced solid tumors.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Is willing and able to provide written informed consent for the trial.
2. Is at ≥ 18 years of age on day of signing informed consent.
3. Has a histologically confirmed advanced solid tumor. Subjects must have received at least 2 doses of an approved anti-PD-1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies, and have documented progression on or within 12 weeks from the last dose of anti-PD-1/L1 mAb.
4. Has received standard of care or is intolerant of, refuses, or is not eligible for standard of care antineoplastic therapy.
5. Has at least 1 measurable disease lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST).
6. Is willing to safely undergo tissue biopsies of involved tissue, if required. However, if the Investigator considers that a tissue biopsy is not safe and/or not technically feasible, then the subject will not be required to undergo the biopsy.
a. The Screening biopsy must be performed prior to the first dose of BI 1206 (on non-previously irradiated lesions only), and at least 4 weeks following the last dose of tumor-directed therapy. The biopsy at Screening can be replaced with a formalin- fixed archival tumor tissue sample collected from a previous standard of care biopsy, provided that the biopsy was performed after the subject’s last tumor- directed therapy and prior to study entry. Subjects who do not have an archival tissue sample at Screening may still be enrolled in the study.
7. Has a life expectancy of ≥12 weeks.
8. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1.
9. Has adequate organ function as confirmed by laboratory values listed in the main body of the protocol.
Expansion Cohort-specific Inclusion Criteria:
In addition to the general inclusion criteria above, subjects must also meet the criteria for the specific cohort. Additional requirements will be added based on learnings from subjects enrolled in the Phase 1 portion of the trial.
1. Cohort 1 (Non-small- cell lung cancer):
a.For subjects whose tumor has PD-L1 ≥50%: Required prior therapies will include anti-PD-1 therapy as monotherapy. Prior standard of care (SOC) chemotherapy will be allowed but not required.
b. For tumors with unknown PD-L1 or PD-L1 <50% , required prior therapies will include anti-PD 1/PD-L1 therapy and SOC chemotherapy either combined with anti PD-1/PD-L1 therapy or given separately.
c. For subjects with known anaplastic lymphoma kinase (ALK), ROS proto- oncogene 1, receptor tyrosine kinase (ROS1) or epidermal growth factor receptor (EGFR) sensitizing molecular rearrangements, or with BRAF mutations, at least 1 line of targeted therapy will be required in addition to anti-PD-1/PD-L1 therapy.
2. Cohort 2 (Metastatic Melanoma):
a. Required prior therapies will include anti-PD-1 therapy either as monotherapy or as part of a combination regimen.
b. For subjects with a known BRAF V600-activating mutation combination targeted therapy will be required in addition to anti-PD-1/PD-L1 therapy.
3. Cohort 3 (Other Tumor Types):
a. All subjects will require prior anti-PD-1/PD-L1 therapy. |
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| E.4 | Principal exclusion criteria |
1. Needs doses of prednisolone >10 mg daily (or equipotent doses of other corticosteroids) while on the trial other than as premedication. During the Screening period, doses of up to 20 mg/day may be given but the dose must be reduced to 10 mg/day within 7 days prior the first dose of study drug. Steroids are allowed as premedication in subjects with allergies to contrast scans.
2. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated CNS metastases may participate provided they are radiologically stable (without evidence of progression for at least 4 weeks by repeat imaging [performed during study Screening]); have no newly-onset or worsening symptomatology of brain metastases; and have not required steroids for at least 14 days before study treatment.
3. Has known or suspected hypersensitivity to pembrolizumab or BI-1206 or any of their excipients. Previous isolated IRRs are not to be considered a reason for exclusion unless Grade 4 in intensity.
4. Has cardiac or renal amyloid light-chain amyloidosis.
5. Has received the following:
• Chemotherapy or small molecule products within 4 weeks of first dose of BI-1206.
• Radiotherapy within 2 weeks of first dose of BI-1206. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) for non-CNS disease. Subjects who have previously had radiation pneumonitis are not allowed.
• Immunotherapy within 4 weeks prior to the first dose of BI-1206.
6. Has not recovered from adverse events (AEs) to at least Grade 1 by CTCAE v5.0 due to prior anti-cancer therapies. Exceptions are alopecia or certain Grade 1 toxicities, which in the opinion of the Investigator should not exclude the subject. Subjects with ≤Grade 2 neuropathy may be eligible, after discussion with the Medical Monitor.
7. Has had Grade ≥3 autoimmune manifestations of previous immune checkpoint inhibitor treatments (e.g. anti-PD1, anti-PDL1 or anti-CTLA4).
8. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
9. Has an active, known or suspected autoimmune disease. Subjects with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, mild psoriasis, or alopecia not requiring systemic treatment), or conditions not expected to recur in the absence of an external trigger will be permitted to participate.
10. Is a female subject and has the ability to become pregnant (or already pregnant or lactating/ breastfeeding). Those female subjects who have a negative serum or urine pregnancy test before enrollment and agree to use a highly effective method of birth control for 4 weeks before entering the trial, during the trial and for 12 months after last dose of BI-1206 are considered eligible. Highly effective methods of birth control are defined in protocol.
11. Is a male subject with partner(s) of childbearing potential use a barrier method of contraception [condom plus spermicidal gel] with the female partner(s) who are using one highly effective method of contraception during the trial and for 12 months after completing treatment). Men with pregnant or lactating partners should be advised to use barrier method contraception (condom plus spermicidal gel).
12. Has had major surgery from which the subject has not yet recovered.
13. Is at high medical risk because of non-malignant systemic disease including severe active infections on treatment with antibiotics, antifungals or antivirals.
14. Has presence of chronic graft versus host disease.
15. Has had an allogenic tissue/solid organ transplant.
16. Has known human immunodeficiency virus (HIV) and/or history of hepatitis B or C infections, or has a positive test for HIV Ab, hepatitis B antigen/hepatitis B virus DNA or hepatitis C Ab or RNA.
17. Has a history of active tuberculosis (bac. tuberculosis).
18. Has received a live vaccine within 30 days before the first dose of study treatment. COVID-19 vaccines based on viral RNA or protein fragments, or killed viruses, are allowed. COVID 19 vaccines based on live replicating viral or bacterial vectors are not allowed.
19. Has uncontrolled or significant cardiovascular disease as per protocol definition.
20. Has a known psychiatric or substance abuse disorder that would interfere with the subject’s ability to cooperate with the requirements of the study.
21. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the Investigator.
22. Is participating or planning to participate in another interventional clinical trial, or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to first dose of study drug. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1) Documentation of AEs and SAEs (graded according to National Cancer Institute [NCI]-CTCAE version 4.0) and significant laboratory parameters and physical findings and their causality to BI-1206 and/or pembrolizumab.
2) Determination of RP2D and the MTD or maximum administered dose of BI-1206, based on the modified mTPI-2 design. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) Throughout study.
2) The totality of the data on PK, PD, and safety emerging throughout the study's first part (phase 1) will be considered by the Cohort Review Committee to determine the MTD and recommend the dose for Part 2
(phase 2a). |
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| E.5.2 | Secondary end point(s) |
1) Determination of standard PK parameters (i.e., AUC, Cmax, Tmax, and half-life [t½]) for BI-1206.
2) Measurement of ADA response to BI-1206.
3) Blood exploratory samples. Measurement of CD32b receptor occupancy on B cells. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) IV infusion: Cycle 1: day 2, 3, 4, 6, 10, 17. Cycle 2: day 23, 24. Cycle 3: day 44, 45, 46, 48, 52.
SC injection once/cycle: Dose 1: day 2-7, 9, 16. Dose 2: day 23. Dose 3: day 44-49, 51.
SC injection twice/cycle: Cycle 1: day 2-7, 9-11, 13, 16. Cycle 2: day 23, 30. Cycle 3: day 44-49, 51.
All: Week 9, Day 58. Week 10, every 3w for additional doses. 30, 56, 90 days after last dose of BI-1206 (EOT, OTFU 1, OTFU2 respektively)
2) Cycle 1: day 2. Cycle 2: day 23. Cycle 3: day 44. Week 10 and every 3 wk for additional doses. 30, 56, 90 days after last dose of BI-1206 (EOT, OTFU 1, OTFU2 respektively)
3) IV infusion: Cycle 1: day 2, 3, 4. Week 9, Day 58
SC injection: Cycle 1: day 2, 3, 9. Week 9, Day 58 |
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| 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 | Yes |
| 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 |
| Dose-finding with dose escalation cohorts and selection of the recommended Phase 2 dose |
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| 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.8.3 |
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 | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
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| 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
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The ‘end of trial’ is defined as the date when the last subject has received their last BI-1206 treatment and completed the off-treatment follow-up 2 visit.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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