JOURNAL ONKOLOGIE – STUDIE

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

Studien-Informationen Einschlusskriterien Studien-Rationale Studien-Arme Geprüfte Regime

Rekrutierend

NCT-Nummer:
NCT03252938

Studienbeginn:
August 2017

Letztes Update:
06.03.2024

Wirkstoff:
IMP321, Avelumab

Indikation (Clinical Trials):
Carcinoma, Peritoneal Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 1

Sponsor:
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Collaborator:
-

Studienleiter

Thorsten Götze, MD
Principal Investigator
Institute of Clinical Cancer Research (IKF), UCT Frankfurt, Germany

Kontakt

Salah-Eddin Al-Batran, MD
Kontakt:
Phone: +49 69 7601
Phone (ext.): 4420
E-Mail: albatran@ikf-khnw.de» Kontaktdaten anzeigen

Sabine Beck, PhD
Kontakt:
Phone: +49 69 7601
Phone (ext.): 3955
E-Mail: beck.sabine@ikf-khnw.de» Kontaktdaten anzeigen

Studienlocations
(3 von 8)

Helios Klinikum Bad Saarow
15526 Bad Saarow
(Brandenburg)
GermanyRekrutierend» Google-Maps

Onkologisches Zentrum Krankenhaus Nordwest
Steinbacher Hohl 2-26
60488 Frankfurt am Main
DeutschlandRekrutierend» Google-Maps
Ansprechpartner:
Thorsten O. Götze, Prof. Dr.
Phone: +4969 7601
Phone (ext.): 4420
E-Mail: Goetze.Thorsten@KHNW.DE

Sabine Beck, PhD
Phone: +4969 7601
Phone (ext.): 3955
E-Mail: beck.sabine@ikf-khnw.de» Ansprechpartner anzeigen

Hämatologisch Onkologische Praxis Eppendorf (HOPE)
20249 Hamburg
(Hamburg)
GermanyRekrutierend» Google-Maps

Marienhospital Herne, Klinik der Ruhr Universität Bochum, Klinik für Urologie
44625 Herne
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps

Kliniken der Stadt Köln gGmbH, Studienzentrum der Lungenklinik, Krankenhaus Merheim
51109 Köln
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps

Universitätsmedizin der Johannes Gutenberg-Universität Mainz
55131 Mainz
(Rheinland-Pfalz)
GermanyRekrutierend» Google-Maps

Viszeralonkologisches Zentrum Universitätsklinikum Tübingen
Hoppe-Seyler-Straße 3
72076 Tübingen
DeutschlandRekrutierend» Google-Maps

Universitätsklinikum Ulm, Early Clinical Trials Unit (ECTU)
89081 Ulm
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps

Alle anzeigen

Studien-Informationen

Detailed Description:

Up to now, IMP321 is solely administered by sub-cutaneous injection (e.g. on the anterior

face of the thigh). In this study, we investigate whether a direct injection of IMP321 into

the tumor tissue will be a useful option to improve anti-tumor immune response by placing the

immune-therapeutic agent in direct vicinity of immune infiltrates in the tumor bed. This

bypasses processes necessary for drug delivery to cells of solid tumors following systemic

administration, like transport within vessels, transport across vasculature walls into

surrounding tissues, and - in cases of peritoneal metastases - transport through the

interstitial space within a tumor. For the latter case, we will also explore if an

intra-peritoneal therapy represents a feasible alternative by means of delivering high drug

concentrations directly to tumors located in the peritoneal cavity.

Furthermore, we will explore the possibility to extend the positive results obtained by

subcutaneous injections of IMP321 in metastatic renal cell and breast carcinomas to further

solid tumor entities. In this part of the study, patients will be treated with the

standard-of-care (SOC) chemotherapy and/or immunotherapy/targeted therapy for their tumor

entity along with subcutaneous injections of IMP321.

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Histologically confirmed locally advanced (not manageable with curative intent) or

metastatic solid tumor Specification for Stratum C: Only patients with NSCLC

adenocarcinomas, (squamous or adenosquamous not permitted) who are scheduled to

receive platin + pembrolizumab + pemetrexed standard treatment (only for Stratum C)

Specification for Stratum E: Including only metastatic or irresectable locally

advanced urothelial carcinomas - also refer to IC#15 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 intolerable towards

standard therapy (Strata A, B, and D) or who receives Standard-of-Care first line

treatment comprising platin + pembrolizumab + pemetrexed (only for Stratum C)

5. Patient has not received more than 4 prior lines of therapy. Neoadjuvant/adjuvant

treatment is not counted unless progression occurs <6 months after completion of the

treatment. In these cases, neoadjuvant/adjuvant treatment is counted as one prior line

(only for Stratum D).

Specification for Stratum C: Only patients receiving first line Standard-of-Care

therapy (platin + pembrolizumab + pemetrexed; only for Stratum C) Specification for

Stratum E: Refer to IC#15 below with regards to previous lines of therapy; only for

Stratum E) Note exclusion criterion #7 on exclusion of defined previous cancer

immunotherapy (only for Strata D and E)

6. Patients ≥ 18 years. Patients in reproductive age must be willing to use highly

effective contraception during the study and 4 months after the end of the study

(appropriate contraception is defined as combined (estrogen and progestogen

containing) hormonal contraception associated with inhibition of ovulation,

progestogen-only hormonal contraception associated with inhibition of ovulation,

intrauterine device (IUD), intrauterine hormone-releasing system (IUS), vasectomized

partner, bilateral tubal occlusion, sexual abstinence. If an oral contraception is

used, a barrier method of contraception (e.g. male condom, female condom, cervical

cap, diaphragm, contraceptive sponge) has to be applied additionally.). Female

patients with childbearing potential need to have a negative pregnancy test within 7

days 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

- 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 (unless

receiving anticoagulation therapy). Patients receiving warfarin/ phenprocoumon must be

switched to low molecular weight heparin and have achieved stable coagulation profile.

10. Patient able and willing to provide written informed consent and to comply with the

study protocol and with the planned surgical procedures

11. Evidence of measurable disease as defined by RECIST v1.1 (only for Strata C, D and E)

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 (except

for 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 be

eligible for platinum-based therapy AND has a PD-L1 CPS ≥10 or

- did not receive any prior systemic therapy for metastatic disease AND is not

eligible for platinum-based therapy, independent from PD-L1 CPS status or

- did suffer disease progression during/directly after a platinum-based

chemotherapy for metastatic disease AND did not receive avelumab maintenance

therapy 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 drug

into parenchymatous organs such as, but limited to liver, spleen or pancreas (only for

Stratum A)

3. Patients with contraindication versus a laparoscopy or refusing a laparoscopy (only

for Stratum B)

4. Hypersensitivity towards eftilagimod alpha, avelumab (only for Strata D and E), or any

ingredient of the injection/infusion solutions

5. History of severe allergic, anaphylactic, or other hypersensitivity reactions to

chimeric or humanized antibodies or fusion proteins

6. Currently receiving any other antineoplastic treatment including irradiation, or

targeted small molecule therapy, or biological cancer therapy, or less than 4 weeks

since completion of these therapies and first dose of study treatment (only Strata A,

B, D and E)

7. Prior PD-1/PDL-1 targeted therapy (only for Strata D and E). NOTE: For Stratum E only,

patients can be enrolled if they received prior PD-1/PD-L1 targeted therapy during

neoadjuvant treatment. HOWEVER, only after at least a free interval of at least 12

months after neoadjuvant PD-1/PD-L1 addressed- therapy.

8. Cirrhosis of the liver (Child > Grade A), pronounced alcohol abuse with anticipated

detoxification, severe pulmonary infection with considerable reduction of pulmonary

function

9. Clinically significant active coronary heart disease, cardiomyopathy or congestive

heart failure, NYHA III-IV (for Stratum D: ≥ NYHA II) within 6 months prior to first

dose of study treatment including: myocardial infarction, severe/unstable angina,

ongoing cardiac dysrhythmias of current NCI CTCAE version Grade >2, atrial

fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic

congestive heart failure, cerebrovascular accident including transient ischemic

attack, ventricular arrhythmias requiring medication or symptomatic pulmonary embolism

10. Cerebral or leptomeningeal metastases Note: Subjects with previously treated brain

metastases may participate if they meet the following criteria: 1) are stable for at

least 28 days prior to the first dose of study treatment and if all neurologic

symptoms returned to baseline; 2) have no evidence of new or enlarging brain

metastases; and 3) have not been using steroids for at least 7 days prior to first

dose of study treatment. This exception does not include carcinomatous meningitis

which is excluded regardless of clinical stability.

11. Chronic inflammatory bowel disease

12. Active infection requiring systemic therapy at the start of study treatment or chronic

infection or serious intercurrent infection within 4 weeks prior to first dose of

study treatment

13. QTcF >480 ms, family or personal history of long or short QT syndrome, Brugada

syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP)

14. Uncontrolled electrolyte disorders that can worsen the effects of a QTc-prolonging

drug (e.g., hypocalcaemia, hypokalaemia, hypomagnesemia)

15. Positive test for human immunodeficiency virus (HIV) or known acquired

immunodeficiency syndrome. Testing is not required in the absence of history.

Participants with known human immunodeficiency virus (HIV) infections are eligible if

the following criteria are met:

1. If clinically indicated participants must be stable on antiretroviral therapy

(ART) for at least 4 weeks and agree to adhere to ART. If not clinically

indicated, consult Principal Investigator (LKP).

2. Participants with HIV infection should have no evidence of documented multidrug

resistance that would prevent effective ART.

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

4. If prophylactic antimicrobial drugs are indicated, patient may still be

considered eligible upon agreement with the Principal Investigator (LKP)

16. 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 or

resolved HBV infection (defined as having a negative HBsAg test and a positive

antibody to hepatitis B core antigen antibody test) are eligible. Note: Patients

positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain

reaction testing is negative for HCV ribonucleic acid (RNA). Testing is not required

in the absence of history.

17. History or evidence of interstitial lung disease, active non-infectious pneumonitis or

active tuberculosis

18. Active or prior autoimmune disease requiring immunosuppressive therapy that might

deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I,

vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive

treatment are eligible.

19. Known history of immune-mediated colitis, pneumonitis, pulmonary fibrosis (only for

Strata D and E).

20. Administration of a live, attenuated vaccine (including Covid-19 vaccination with

live, attenuated vaccine) within four weeks prior to start of treatment or

anticipation that such a live attenuated vaccine will be required during the remainder

of the study.

21. 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 topical steroids, 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 daily prednisone

equivalent are permitted in the absence of active autoimmune disease.

22. Treatment with systemic immunostimulatory agents (including but not limited to

interferons or interleukin-2) within four weeks or five half-lives of the drug,

whichever is shorter, prior to start of study treatment

23. Any previous venous thromboembolism > National Cancer Institute (NCI) Common

Terminology Criteria for Adverse Events (CTCAE) Grade 3 within the last 6 months

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

25. Prior organ transplantation or stem cell transplantation

26. On-treatment participation in another clinical study in the period 30 days prior to

start of study treatment and during the study

27. Patients in a closed institution according to an authority or court decision (AMG §

40, Abs. 1 No. 4)

28. Pregnancy or lactation

29. Planned intratumoral injections in parenchymatous organs (e.g. liver, spleen, adrenal

gland, pancreas)

30. Life-threatening illness unrelated to cancer

31. History of irAEs of CTCAE Grade 4 requiring steroid treatment (only for Strata C, D

and E)

32. Persisting toxicity related to prior therapy (NCI CTCAE current version Grade > 1);

however, alopecia, sensory neuropathy Grade ≤2, or other Grade ≤2 AEs not constituting

a safety risk based on investigator's judgment are acceptable (only for Strata D and

E)

33. Other severe acute or chronic medical conditions, psychiatric conditions including

recent (within the past year) or active suicidal ideation or behavior; or laboratory

abnormalities that may increase the risk associated with study participation or study

treatment 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.

Studien-Rationale

Primary outcome:

1. Feasibility rate (Time Frame - 10 weeks of treatment + 2 weeks of safety observation period):
Rate of patients receiving the protocol treatment without occurrence of a dose limiting toxicity

Secondary outcome:

1. Incidence and severity of adverse events according to CTC criteria (Time Frame - 12 months of treatment + 12 months of Follow Up):
Incidence and severity of adverse events according to the current National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).

2. Response (Time Frame - 12 months of Follow Up):
Objective response rate according to RECIST 1.1 and endoscopic response criteria

3. Progression free survival (Time Frame - 12 months of Follow Up):
PFS will be measured as time from inclusion until disease progression or death of any cause

4. Overall survival (Time Frame - 12 months of Follow Up):
OS will be measured as time from inclusion to death of any cause

5. Immune response in whole blood and tumor tissue (Time Frame - 12 months of treatment + 12 months of Follow Up):
Peripheral blood monocyte number and CD8 T-cell number, associated activation markers, tumor-infiltrating immune cells

Studien-Arme

Experimental: Solid tumors
Biweekly intra-tumoral injections of escalating doses (6 mg, 12 mg, 24 mg and 30 mg) of IMP321 as a monotherapy (intratumoral injections in parenchymatous organs (e.g. liver, spleen, adrenal gland, pancreas) are not allowed)
Experimental: Solid tumors + peritoneal carcinomatosis
Biweekly intra-peritoneal, escalating doses of IMP321 (1 mg, 3 mg, 6 mg, 12 mg and 30 mg)
Experimental: Solid tumors + chemotherapy
Subcutaneous (s.c.) injections with the optimal dose of IMP321 defined in the AIPAC trial for a maximum of 24 weeks
Experimental: Solid tumors + Avelumab/IMP321 therapy
Avelumab and IMP321 as follows: 800 mg avelumab every 2 weeks i.v. (for a maximum of 24 cycles [48 weeks]) 6 mg (cohort 1) or 30 mg (cohort 2) IMP321 every 2 weeks s.c. (for a maximum of 12 cycles [24 weeks])
Experimental: Solid tumors + Avelumab/IMP321 combination therapy
Avelumab and IMP321 as follows: • 800 mg avelumab every 2 weeks i.v. and 30 mg IMP321 every 2 weeks s.c. for a maximum of 24 cycles [12 months]

Geprüfte Regime

IMP321 (LAG-3Ig fusion protein):
LAG-3Ig fusion protein, highly potent activator of antigen presenting cells
Avelumab:
Avelumab i.v.

Quelle: ClinicalTrials.gov

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