Phase 1/2a Open-Label, Dose-Escalation, Multicenter, First in-Human, Consecutive-Cohort, Clinical Trial of BI 1910, a Monoclonal Antibody to Tumor Necrosis Factor Receptor 2 (TNFR2), as a Single Agent and in Combination with Pembrolizumab in Subjects with Advanced Solid Tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Bioinvent International AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

4 Dec 2023 → 18 Dec 2025

Decision date (initial)

2023-11-14

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

BioInvent International AB

External identifiers

EU CT number

2022-503066-74-00

WHO UTN

U1111-1293-2634

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacogenomic, Safety, Dose response, Pharmacokinetic, Efficacy, Diagnosis

To assess the safety and tolerability profile of BI- 1910 as a single agent and in combination with pembrolizumab in subjects with advanced solid tumors.
Phase 1: To determine the maximum tolerated dose (MTD) or maximum administered safe dose (MAD) of BI-1910, as a single agent, and in combination with pembrolizumab.
Phase 2a: To determine the recommended Phase 2 dose(s) (RP2D[s]) for further clinical trials.

Secondary objectives 4

1. Phases 1 and 2a: To characterize the PK profile of BI-1910 when administered every 3 weeks as a single agent, and in combination with pembrolizumab.
2. Phase 1: To determine the recommended dose range (RDR).
3. Phases 1 and 2a: To assess the immunogenicity of BI 1910.
4. Phase 2a: To assess preliminary antitumor activity as measured by RECIST 1.1 and iRECIST, as a single agent, and in combination with pembrolizumab.

Conditions and MedDRA coding

Advanced solid tumors

Study design 4 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Is willing and able to provide signed informed consent for the trial. If the subject does not consent to the genetic testing they may still participate in the trial.
2. 2. Is ≥18 years of age on the day of signing the informed consent form (ICF).
3. 3. Has a histologically confirmed advanced/metastatic solid tumor.
4. 4. Has received standard of care and progressed or is intolerant of, or is not eligible to receive standard of care antineoplastic therapy.
5. 6. Has at least 1 measurable disease lesion as defined by RECIST v1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
6. 7. Must be willing to provide tumor biopsies as specified in the schedule of assessments unless otherwise discussed and agreed with the Sponsor in case a biopsy cannot be taken for a medical/safety reason. The Screening biopsy must be performed prior to the first dose of BI-1910 (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 trial entry.
7. 8. Has a life expectancy of ≥12 weeks.
8. 9. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
9. 10. Has adequate organ function as confirmed by laboratory values
10. 11.Subjects who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. Note: Subjects should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention. Hepatitis B screening tests are not required unless: • Known history of HBV infection • As mandated by local health authority
11. 12. Subjects with history of HCV infection are eligible if HCV viral load is undetectable at screening. Note: Subjects must have completed curative anti-viral therapy at least 4 weeks prior to randomization. Hepatitis C screening tests are not required unless: • Known history of HCV infection • As mandated by local health authority
12. 5. For subjects who received an anti-PD-1/L1 mAb: a. Has received at least 2 doses of an approved anti-PD-1/L1 mAb. b. Has demonstrated disease progression after anti-PD-1/L1-containing treatment as defined by RECIST v1.1. c. Progressive disease has been documented within 12 weeks from the last dose of anti-PD-1/L1 mAb.

Exclusion criteria 26

1. 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 to the first dose of study treatment. Steroids are allowed as premedication in subjects with allergies to contrast scans.
2. 11. Is a female subject and has the ability to become pregnant (or already pregnant or lactating/breastfeeding). However, those female subjects who have a negative serum or urine pregnancy test up to 72 hours prior to their first dose of study treatment 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 their last dose of study treatment (BI 1910 or pembrolizumab), are considered eligible. Highly effective methods of birth control include: a. Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: i. Oral ii. Intravaginal iii. Transdermal b. Progestogen-only hormonal contraception associated with inhibition of ovulation: i. Oral ii. Injectable iii. Implantable c. Intrauterine device d. Intrauterine hormone-releasing system e. Bilateral tubal occlusion f. Vasectomized partner (given that the partner is the sole sexual partner of the subject and that the vasectomized partner has received medical assessment of the surgical success). g. Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the preferred and usual lifestyle of the subject). Note: A woman of childbearing potential is defined as any female who has experienced menarche, who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy), and who is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 in the absence of other biological or physiological causes. In addition, females under the age of 55 years must have a documented serum follicle-stimulating hormone level >40 mIU/mL to confirm menopause.
3. 12. Is a male subject with partner(s) of childbearing potential (unless he agrees to 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) to prevent exposure to the fetus or neonate. All males should refrain from sperm donation for 12 months after last dose of study treatment.
4. 13. Has had major surgery from which the subject has not yet recovered.
5. 14. Is at high medical risk because of nonmalignant systemic disease including severe active infections on treatment with antibiotics, antifungals, or antivirals other than the ones considered adequate for treatment of HBV.
6. 15. Has presence of chronic graft versus host disease.
7. 16. Has had an allogenic tissue/solid organ transplant.
8. 17. Is positive for Human Immunodeficiency Virus (HIV).
9. 18. Has a history of active tuberculosis (Bacillus tuberculosis).
10. 19. Has received a live vaccine within 30 days before the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. Similarly, COVID-19 vaccines based on viral RNA or protein fragments are allowed. COVID 19 vaccines based on live replicating viral or bacterial vectors (e.g., adenoviruses, adeno-associated viruses, vesicular stomatitis virus, vaccinia viruses, or measles virus) are not allowed.
11. 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 [note that the repeat imaging should be performed during trial Screening]); have no newly onset or worsening symptomatology of brain metastases; and have not required steroids for at least 14 days before study treatment.
12. 20. Has uncontrolled or significant cardiovascular disease including, but not limited to, any of the following: a. Myocardial infarction or stroke/transient ischemic attack within the past 6 months b. Uncontrolled angina within the past 3 months c. Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes). An exception to this criterion is atrial fibrillation with satisfactory cardiac function. d. QT interval prolongation >480 milliseconds (corrected for heart rate using Fridericia’s formula) e. History of other clinically significant heart disease (e.g., cardiomyopathy, congestive heart failure with New York Heart Association functional classification III-IV, pericarditis, significant pericardial effusion, or myocarditis).
13. 21. Has a known psychiatric or substance abuse disorder that would interfere with the subject’s ability to cooperate with the requirements of the trial.
14. 22. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
15. 23. 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 treatment. Subjects who have entered the follow up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. Participation in an observational trial is acceptable. Subjects who have participated in this clinical trial (22 BI 1910-01) cannot be re-enrolled into another phase of the trial.
16. 24. Has a known additional malignancy of another type, with the exception of adequately treated cone biopsied carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) and basal or squamous cell carcinoma of the skin. Male subjects with asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for >1 year prior to start of study treatment are eligible. Subjects who have undergone potentially curative therapy for a prior malignancy, have no evidence of disease for ≥3 years, and are deemed at negligible risk for recurrence, are also eligible.
17. 25. Has a confirmed diagnosis of primary immunodeficiency or an acquired condition that leads to an immunodeficiency disorder or taking any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment.
18. 26. Is unable to attend the trial site to receive the study treatment.
19. 3. Has known or suspected hypersensitivity to BI-1910 (all subjects) or pembrolizumab (subjects in Phase 1 Part B and Phase 2a Part B) or any of their excipients. Previous isolated IRRs are not to be considered a reason for exclusion unless Grade 4 in intensity.
20. 5. Has cardiac or renal amyloid light-chain amyloidosis.
21. 6. Has received the following: a. Systemic chemotherapy or small molecule anti- cancer therapy products within 4 weeks, or 5 half-lives of the respective drug whichever is longer, of first dose of BI- 1910. b. Radiotherapy within 2 weeks of first dose of BI-1910. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) for noncentral nervous system disease. Subjects who have previously had radiation pneumonitis are not allowed. c. Biological anti-cancer therapy products within 4 weeks prior to the first dose of BI- 1910.
22. 7. Has not recovered from AEs deemed greater Grade 1 by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v5.0 or higher) due to prior anticancer therapies. Exceptions to this 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 and the Sponsor.
23. 8. Has had Grade ≥3 autoimmune manifestations due to previous immune checkpoint inhibitor treatments (e.g., anti–PD-1, anti–PD-L1, or anti–CTLA-4). Exceptions to this are adverse events with short duration, managed and resolved with adequate medicinal intervention, or where the subject could be rechallenged with immune checkpoint inhibitor treatment without further events. Exceptions must be agreed to between the Investigator and Sponsor.
24. 9. Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
25. 10. Has an active, known, or suspected autoimmune disease. However, 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.
26. 4. Has symptomatic pleural, pericardial or peritoneal fluid effusions that require treatment or surgical intervention.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Phases 1 and 2a: -Occurrence of adverse events (AEs) or serious adverse events (SAEs). -Changes from baseline in laboratory parameters, vital signs, and physical findings. - Frequency of dose interruptions and dose reductions. -Frequency of AEs leading to discontinuation of study treatment(s).
2. Phase 1: Occurrence of dose limiting toxicities (DLTs).
3. Phase 2a: Identification of dose/dose range fulfilling favorable pharmacokinetic (PK) and pharmacodynamic profile, with acceptable safety (based on the totality of the efficacy, safety, PK, and pharmacodynamic endpoint

Secondary endpoints 3

1. Phases 1 and 2a: -Calculated standard PK parameters for BI 1910 (including, but not limited to, area under the serum concentration-time curve [AUC], maximum concentration [Cmax], and terminal half-life [t½]). -Incidence and titer of antidrug antibodies (ADAs).
2. Phase 1: RDR is defined as the range between MRAD and the MTD/MAD. MRAD is the lowest dose level at which at least 2 subjects experience ≥10% tumor shrinkage and/or relevant PK/PD parameters indicate biological activity: - Response based on RECIST 1:1 and iRECIST. - PK parameters AUC, Cmax, t½. - PD biomarkers such as TNFR2 receptor occupancy immune activation parameters, sTNFR2 and cytokine profiles
3. Phase 2a: - Objective response rate (ORR). - Duration of response (DoR).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Bioinvent International AB

Sponsor organisation

Bioinvent International AB

Address

Ideongatan 1 A

City

Lund

Postcode

223 70

Country

Sweden

Scientific contact point

Organisation

Bioinvent International AB

Contact name

Mindaugas Meller

Public contact point

Organisation

Bioinvent International AB

Contact name

Mindaugas Meller

Third parties 9

Locations

5 EU/EEA countries · 10 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 39 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications