Feasibility and Safety of IMP321 for Advanced Stage Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03252938
Recruitment Status : Recruiting
First Posted : August 17, 2017
Last Update Posted : January 9, 2018
Information provided by (Responsible Party):
IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest

Brief Summary:
This phase I trial aims to investigate a potential enhancement of IMP321 immune-activating effects by new routes of administration: direct injection of IMP321 into the tumor tissue; intra-peritoneal therapy; combination of chemotherapy with active immunotherapy (chemo-immunotherapy)

Condition or disease Intervention/treatment Phase
Solid Tumors Peritoneal Carcinomatosis Drug: IMP321 Phase 1

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 for their tumor entity along with subcutaneous injections of IMP321.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Explorative, Single Center, Open-labeled, Phase I Study to Evaluate the Feasibility and Safety of Intra-tumoral, Intra-peritoneal, and Subcutaneous Injections With IMP321 (LAG-3Ig Fusion Protein) for Advanced Stage Solid Tumor Entities
Actual Study Start Date : August 15, 2017
Estimated Primary Completion Date : February 2019
Estimated Study Completion Date : February 2019

Arm Intervention/treatment
Experimental: Solid tumors
Biweekly intra-tumoral injections of escalating doses (6 mg, 12 mg, 24 mg and 30 mg) of IMP321 as a monotherapy
Drug: IMP321
LAG-3Ig fusion protein, highly potent activator of antigen presenting cells
Other Name: LAG-3Ig fusion protein

Experimental: Solid tumors + peritoneal carcinomatosis
Biweekly intra-peritoneal, escalating doses of IMP321 (1 mg, 3 mg, 6 mg, 12 mg and 30 mg)
Drug: IMP321
LAG-3Ig fusion protein, highly potent activator of antigen presenting cells
Other Name: LAG-3Ig fusion protein

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
Drug: IMP321
LAG-3Ig fusion protein, highly potent activator of antigen presenting cells
Other Name: LAG-3Ig fusion protein

Primary Outcome Measures :
  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 Measures :
  1. Incidence and severity of adverse events according to CTC criteria [ Time Frame: 10 weeks of treatment + 6 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: 6 months of Follow Up ]
    Objective response rate according to RECIST 1.1 and endoscopic response criteria

  3. Progression free survival [ Time Frame: 6 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: 6 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: 10 weeks of treatment + 6 months of Follow Up ]
    Peripheral blood monocyte number and CD8 T-cell number, associated activation markers, tumor-infiltrating immune cells

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Histologically confirmed locally advanced or metastatic solid tumor
  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) or who receives standard-of-care chemotherapy indicated for his/her tumor entity (only for Stratum C)
  5. Patient does not receive a concurrent chemotherapy (only for Strata A and B)
  6. Female and male patients ≥ 18 years. Patients in reproductive age must be willing to use highly effective contraception during the study and 3 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
    • Serum creatinine ≤ 1.5 x upper limit of normal, or GFR ≥ 50 ml/min
    • Bilirubin ≤ 1.5 - 3 x upper limit of normal
    • AST and ALT ≤ 3 x upper limit of normal (≤ 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

Exclusion Criteria:

  1. Inability to understand the aims of the study and/or protocol procedures
  2. Bleeding ulcerative tumors (only for Stratum A)
  3. Patients with contraindication versus a laparoscopy or refusing a laparoscopy (only for Stratum B)
  4. Hypersensitivity to IMP321 or any ingredient of the injection solution
  5. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  6. Any other concurrent antineoplastic treatment including irradiation (only Strata A and B)
  7. Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents
  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
  10. Clinically active brain metastases, defined as untreated symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms.

    Subjects with treated brain metastases that are no longer symptomatic and require no treatment with steroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy and have no evidence of disease progression on imaging studies (MRI/CT scan).

  11. Chronic inflammatory bowel disease
  12. Active infection requiring intravenous antibiotics at the start of study treatment or chronic infection
  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)
  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).
  17. Active tuberculosis
  18. Active autoimmune disease requiring immunosuppressive therapy
  19. Administration of a live, attenuated vaccine within four weeks prior to start of maintenance treatment or anticipation that such a live attenuated vaccine will be required during the remainder of the study.
  20. Any condition requiring continuous systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 2 weeks prior to first dose of study treatment. Inhaled or topical steroids and physiological replacement doses of up to 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
  21. 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
  22. Any previous venous thromboembolism > National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 within the last 12 months
  23. Past history of severe allergic episodes and/ or Quincke's oedema
  24. Prior organ transplantation or stem cell transplantation
  25. On-treatment participation in another clinical study in the period 30 days prior to start of study treatment and during the study
  26. Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)
  27. Pregnancy or lactation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03252938

Contact: Salah-Eddin Al-Batran, MD +49 69 7601 ext 4420
Contact: Regina Eickhoff, PhD +49 69 7601 ext 4165

Krankenhaus Nordwest Recruiting
Frankfurt, Germany, 60488
Contact: Salah-Eddin Al-Batran, MD    +4969 7601 ext 4420   
Contact: Eickhoff Regina, PhD    +4969 7601 ext 4165   
Principal Investigator: Salah-Eddin Al-Batran, MD         
Sponsors and Collaborators
IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest
Principal Investigator: Salah-Eddin Al-Batran, MD Institute of Clinical Cancer Research (IKF), UCT - University Cancer Center, Frankfurt, Germany

Responsible Party: IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest Identifier: NCT03252938     History of Changes
Other Study ID Numbers: INSIGHT
First Posted: August 17, 2017    Key Record Dates
Last Update Posted: January 9, 2018
Last Verified: January 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest:
solid tumor
peritoneal carcinomatosis

Additional relevant MeSH terms:
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type