Feasibility and Safety of IMP321 (eftilagimod Alpha) for Advanced Stage Solid Tumors

Inclusion Criteria:

1. Histologically confirmed locally advanced (not manageable with curative intent) ormetastatic solid tumor Specification for Stratum C: Only patients with NSCLCadenocarcinomas, (squamous or adenosquamous not permitted) who are scheduled toreceive platin + pembrolizumab + pemetrexed standard treatment (only for Stratum C)Specification for Stratum E: Including only metastatic or irresectable locallyadvanced urothelial carcinomas - also refer to IC#14 below (only for Stratum E)

2. Tumor is accessible for repeated injections and biopsies (only for Stratum A)

3. Peritoneal carcinomatosis (only for Stratum B)

4. Patient failed standard therapy or refused standard therapy or is intolerabletowards standard therapy (Strata A, B, and D) or who receives Standard-of-Care firstline treatment comprising platin + pembrolizumab + pemetrexed (only for Stratum C)

5. Patient has not received more than 4 prior lines of therapy. Neoadjuvant/adjuvanttreatment is not counted unless progression occurs <6 months after completion of thetreatment. In these cases, neoadjuvant/adjuvant treatment is counted as one priorline (only for Stratum D). Specification for Stratum C: Only patients receiving first line Standard-of-Caretherapy (platin + pembrolizumab + pemetrexed; only for Stratum C) Specification forStratum E: Refer to IC#14 below with regards to previous lines of therapy; only forStratum E) Note exclusion criterion #7 on exclusion of defined previous cancerimmunotherapy (only for Strata D and E)

6. Patients ≥ 18 years. Patients in reproductive age must be willing to use highlyeffective contraception during the study and 4 months after the end of the study (appropriate contraception is defined as combined (estrogen and progestogencontaining) hormonal contraception associated with inhibition of ovulation,progestogen-only hormonal contraception associated with inhibition of ovulation,intrauterine device (IUD), intrauterine hormone-releasing system (IUS), vasectomizedpartner, bilateral tubal occlusion, sexual abstinence. If an oral contraception isused, a barrier method of contraception (e.g. male condom, female condom, cervicalcap, diaphragm, contraceptive sponge) has to be applied additionally.). Femalepatients with childbearing potential need to have a negative pregnancy test within 7days before study start.

7. ECOG 0 or 1

8. Adequate hematological, hepatic and renal function parameters:

• ANC (absolute neutrophil count) ≥ 1.500/µl

• Leukocytes ≥ 3.000/µl

• Platelets ≥ 75.000/µl (for Stratum D: ≥ 100.000/µl)

• Serum creatinine ≤ 1.5 x upper limit of normal, or GFR ≥ 50 ml/min; (notapplicable for patients not eligible for platinum-based therapy in Stratum E)

• Bilirubin ≤ 1.5 - 3 x upper limit of normal (for Stratum D: ≤ 1.5 x ULN)

• AST and ALT ≤ 3 x upper limit of normal (≤ 5 x if liver metastases are present) (for Stratum D: AST and ALT ≤ 2.5 x ULN; ≤ 5 x if liver metastases are present)

• Alkaline phosphatase ≤ 6 x upper limit of normal

• Hemoglobin ≥ 9g/dL

9. Adequate coagulation functions as defined by International Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unlessreceiving anticoagulation therapy). Patients receiving warfarin/ phenprocoumon mustbe switched to low molecular weight heparin (new oral anticoagulants (NOACs) arepermitted) and have achieved stable coagulation profile.

10. Patient able and willing to provide written informed consent and to comply with thestudy protocol and with the planned surgical procedures

11. Evidence of measurable disease as defined by RECIST v1.1 (only for Strata C, D andE) or assessable disease as defined by RECIST v1.1 (only for Stratum C)

12. Expected survival > 3 months

13. Resolution of toxicity associated with prior or current therapy to grade <2 (exceptfor alopecia and transaminases in case of liver metastases)

14. Patient is eligible if one of the following settings applies (only for Stratum E):

• did not receive any prior systemic therapy for metastatic disease AND would beeligible for platinum-based therapy AND has a PD-L1 CPS ≥10 or

• did not receive any prior systemic therapy for metastatic disease AND is noteligible for platinum-based therapy, independent from PD-L1 CPS status or

• did suffer disease progression during/directly after a platinum-basedchemotherapy for metastatic disease AND did not receive avelumab maintenancetherapy after platinum-based chemotherapy, independent from PD-L1 CPS status

Exclusion Criteria:

1. Inability to understand the aims of the study and/or protocol procedures

2. Bleeding ulcerative tumors or tumors requiring intratumoral injections of study druginto parenchymatous organs such as, but limited to liver, spleen or pancreas (onlyfor Stratum A)

3. Patients with contraindication versus a laparoscopy or refusing a laparoscopy (onlyfor Stratum B)

4. Hypersensitivity towards eftilagimod alpha, avelumab (only for Strata D and E), orany ingredient of the injection/infusion solutions

5. History of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric or humanized antibodies or fusion proteins

6. Any concurrent other antineoplastic treatment including irradiation, or targetedsmall molecule therapy, or biological cancer therapy. (only Strata A, B, D and E).

7. Prior PD-1/PDL-1 targeted therapy (only for Strata D and E). NOTE: For Stratum Eonly, patients can be enrolled if they received prior PD-1/PD-L1 targeted therapyduring neoadjuvant treatment. HOWEVER, only after at least a free interval of atleast 12 months after neoadjuvant PD-1/PD-L1 addressed- therapy.

8. Cirrhosis of the liver (Child > Grade A), pronounced alcohol abuse with anticipateddetoxification, severe pulmonary infection with considerable reduction of pulmonaryfunction

9. Clinically significant active coronary heart disease, cardiomyopathy or congestiveheart failure, NYHA III-IV (for Stratum D: ≥ NYHA II) within 6 months prior to firstdose of study treatment including: myocardial infarction, severe/unstable angina,ongoing cardiac dysrhythmias of current NCI CTCAE version Grade >2, atrialfibrillation of any grade, coronary/peripheral artery bypass graft, symptomaticcongestive heart failure, cerebrovascular accident including transient ischemicattack, ventricular arrhythmias requiring medication or symptomatic pulmonaryembolism

10. Cerebral or leptomeningeal metastases Note: Subjects with previously treated brainmetastases may participate if they meet the following criteria: 1) are stable for atleast 28 days prior to the first dose of study treatment and if all neurologicsymptoms returned to baseline; 2) have no evidence of new or enlarging brainmetastases; and 3) have not been using steroids for at least 7 days prior to firstdose of study treatment. This exception does not include carcinomatous meningitiswhich is excluded regardless of clinical stability.

11. Chronic inflammatory bowel disease

12. Active infection requiring systemic therapy at the start of study treatment orchronic infection or serious intercurrent infection within 4 weeks prior to firstdose of study treatment

13. QTcF >480 ms, family or personal history of long or short QT syndrome, Brugadasyndrome or known history of QTc prolongation, or Torsade de Pointes (TdP)

14. Uncontrolled electrolyte disorders that can worsen the effects of a QTc-prolongingdrug (e.g., hypocalcaemia, hypokalaemia, hypomagnesemia)

15. Positive test for human immunodeficiency virus (HIV) or known acquiredimmunodeficiency syndrome. Testing is not required in the absence of history. Participants with known human immunodeficiency virus (HIV) infections are eligibleif the following criteria are met:

16. If clinically indicated participants must be stable on antiretroviral therapy (ART) for at least 4 weeks and agree to adhere to ART. If not clinicallyindicated, consult Principal Investigator (LKP).

17. Participants with HIV infection should have no evidence of documented multidrugresistance that would prevent effective ART.

18. Have an HIV viral load of < 400 copies/mL at Screening.

19. If prophylactic antimicrobial drugs are indicated, patient may still beconsidered eligible upon agreement with the Principal Investigator (LKP)

20. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg]test) or hepatitis C Note: Patients with past hepatitis B virus (HBV) infection orresolved HBV infection (defined as having a negative HBsAg test and a positiveantibody to hepatitis B core antigen antibody test) are eligible. Note: Patientspositive for hepatitis C virus (HCV) antibody are eligible only if polymerase chainreaction testing is negative for HCV ribonucleic acid (RNA). Testing is not requiredin the absence of history.

21. History or evidence of interstitial lung disease, active non-infectious pneumonitisor active tuberculosis

22. Active or prior autoimmune disease requiring immunosuppressive therapy that mightdeteriorate when receiving an immunostimulatory agent. Patients with diabetes typeI, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiringimmunosuppressive treatment are eligible.

23. Known history of immune-mediated colitis, pneumonitis, pulmonary fibrosis (only forStrata D and E).

24. Administration of a live, attenuated vaccine (including Covid-19 vaccination withlive, attenuated vaccine) within four weeks prior to start of treatment oranticipation that such a live attenuated vaccine will be required during theremainder of the study.

25. Any condition requiring continuous systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 4 weeks prior to first dose of study treatment. Intranasal, inhaled or topicalsteroids, eye drops or local steroid injection (eg, intra-articular injection),steroids as premedication for hypersensitivity reactions (eg, computed tomography [CT] scan premedication) and physiological replacement doses of up to 10 mg dailyprednisone equivalent are permitted in the absence of active autoimmune disease.

26. Treatment with systemic immunostimulatory agents (including but not limited tointerferons or interleukin-2) within four weeks or five half-lives of the drug,whichever is shorter, prior to start of study treatment

27. Any previous venous thromboembolism > National Cancer Institute (NCI) CommonTerminology Criteria for Adverse Events (CTCAE) Grade 3 within the last 6 months

28. Past history of severe allergic episodes and/ or Quincke's oedema

29. Prior organ transplantation or stem cell transplantation

30. On-treatment participation in another clinical study in the period 30 days prior tostart of study treatment and during the study

31. Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)

32. Pregnancy or lactation

33. Planned intratumoral injections in parenchymatous organs (e.g. liver, spleen,adrenal gland, pancreas)

34. Life-threatening illness unrelated to cancer

35. History of irAEs of CTCAE Grade 4 requiring steroid treatment (only for Strata C, Dand E)

36. Persisting toxicity related to prior therapy (NCI CTCAE current version Grade > 1);however, alopecia, sensory neuropathy Grade ≤2, or other Grade ≤2 AEs notconstituting a safety risk based on investigator's judgment are acceptable (only forStrata D and E)

37. Other severe acute or chronic medical conditions, psychiatric conditions includingrecent (within the past year) or active suicidal ideation or behavior; or laboratoryabnormalities that may increase the risk associated with study participation orstudy treatment administration or may interfere with the interpretation of studyresults and, in the judgment of the investigator, would make the patientinappropriate for entry into this study.