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Feasibility and Safety of IMP321 for Advanced Stage Solid Tumors

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ClinicalTrials.gov Identifier: NCT03252938
Recruitment Status : Recruiting
First Posted : August 17, 2017
Last Update Posted : June 3, 2019
Sponsor:
Information provided by (Responsible Party):
IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest

Tracking Information
First Submitted Date  ICMJE August 14, 2017
First Posted Date  ICMJE August 17, 2017
Last Update Posted Date June 3, 2019
Actual Study Start Date  ICMJE August 15, 2017
Estimated Primary Completion Date November 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 14, 2017)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03252938 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 30, 2019)
  • 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).
  • Response [ Time Frame: 12 months of Follow Up ]
    Objective response rate according to RECIST 1.1 and endoscopic response criteria
  • 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
  • Overall survival [ Time Frame: 12 months of Follow Up ]
    OS will be measured as time from inclusion to death of any cause
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: August 14, 2017)
  • Safety [ Time Frame: 10 weeks of treatment + 6 months of Follow Up ]
    AEs and SAEs, according to the current National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).
  • Response [ Time Frame: 6 months of Follow Up ]
    Objective response rate according to RECIST 1.1 and endoscopic response criteria
  • 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
  • Overall survival [ Time Frame: 6 months of Follow Up ]
    OS will be measured as time from inclusion to death of any cause
  • 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Feasibility and Safety of IMP321 for Advanced Stage Solid Tumors
Official Title  ICMJE 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
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 and/or immunotherapy/targeted therapy with active immunotherapy
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Solid Tumors
  • Peritoneal Carcinomatosis
Intervention  ICMJE
  • Drug: IMP321
    LAG-3Ig fusion protein, highly potent activator of antigen presenting cells
    Other Name: LAG-3Ig fusion protein
  • Drug: Avelumab
    Avelumab i.v.
Study Arms  ICMJE
  • 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)
    Intervention: Drug: IMP321
  • Experimental: Solid tumors + peritoneal carcinomatosis
    Biweekly intra-peritoneal, escalating doses of IMP321 (1 mg, 3 mg, 6 mg, 12 mg and 30 mg)
    Intervention: Drug: IMP321
  • 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
    Intervention: Drug: IMP321
  • 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])
    Interventions:
    • Drug: IMP321
    • Drug: Avelumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 30, 2019)
50
Original Estimated Enrollment  ICMJE
 (submitted: August 14, 2017)
38
Estimated Study Completion Date  ICMJE September 2020
Estimated Primary Completion Date November 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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, D) or who receives standard-of-care therapy indicated for his/her tumor entity (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)
  6. Patient does not receive a concurrent chemotherapy (only for Strata A, B, D)
  7. Female and male 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. Female patients with childbearing potential need to have a negative pregnancy test within 7 days before study start.
  8. ECOG 0 or 1
  9. Adequate hematological, hepatic and renal function parameters:

    • ANC (absolute neutrophil count) ≥ 1.500/µl (for Stratum D: >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
  10. 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.
  11. Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures
  12. Evidence of measurable disease as defined by RECIST v1.1 (only for Stratum D)
  13. Expected survival > 3 months
  14. Resolution of toxicity associated with prior or current therapy to grade <2 (except for alopecia and transaminases in case of liver metastases)

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 to IMP321, avelumab (only for Stratum D) 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. 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 and D)
  7. Prior PD-1/PDL-1 targeted therapy (only for Stratum D)
  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
  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
  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. 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 Stratum D)
  20. 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.
  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

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. 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 Stratum D) 32. Persisting toxicity related to prior therapy (NCI CTCAE v4.03 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 Stratum D) 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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Salah-Eddin Al-Batran, MD +49 69 7601 ext 4420 albatran@ikf-khnw.de
Contact: Regina Eickhoff, PhD +49 69 7601 ext 4165 eickhoff.regina@ikf-khnw.de
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03252938
Other Study ID Numbers  ICMJE INSIGHT
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: No IPD will be shared.
Responsible Party IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest
Study Sponsor  ICMJE IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Salah-Eddin Al-Batran, MD Institute of Clinical Cancer Research (IKF), UCT Frankfurt, Germany
PRS Account IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP