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Phase 1b Study to Evaluate ATP128, With or Without BI 754091, in Patients With Stage IV Colorectal Cancer (KISIMA-01)

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ClinicalTrials.gov Identifier: NCT04046445
Recruitment Status : Recruiting
First Posted : August 6, 2019
Last Update Posted : October 21, 2019
Sponsor:
Collaborator:
Boehringer Ingelheim
Information provided by (Responsible Party):
Amal Therapeutics

Brief Summary:

This is a multi-center, non-randomised Phase 1b study to evaluate the safety and tolerability of ATP128 alone or in combination with BI 754091.

ATP128 is a self-adjuvanted chimeric recombinant protein vaccine being developed in combination with programmed cell death 1 (PD-1) blockade for the treatment of microsatellite stable (MSS) patients not responding to PD-1 blockade. The PD-1 inhibitor being tested with ATP128 is the BI 754091 compound which belongs to the human immunoglobulin G4 (IgG4) subclass of antibodies.

The Sponsor plans to enrol 32 patients with histologically or cytologically confirmed stage IV colorectal cancer coming form three different patient populations:

  • Cohort 1a: 6 patients with stage IV colorectal cancer (CRC) having failed standard of care (SoC) therapies
  • Cohorts 1b, 2a: 11 patients with stage IV microsatellite stable/mismatch repair-proficient (MSS/MMRp) CRC being in stable disease (SD) or partial response (PR) after first line of SoC (6 months duration at minimum)
  • Cohort 2b: 15 patients with stage IV MSS/MMRp hepatic-limited metastatic CRC

Patients eligible for this study will be enrolled in one of the 4 cohorts depending on their disease:

  • Patients in Cohort 1a will receive ATP128 as single agent
  • Patients in Cohorts 1b, 2a will receive ATP128 in combination with BI 754091
  • Patients in Cohorts 2b will receive ATP128 in combination with BI 754091 before and after the liver surgery

Condition or disease Intervention/treatment Phase
Colorectal Cancer MSS Stage IV Colon Cancer Stage IV Rectal Cancer Metastatic Colorectal Cancer Liver Metastasis Colon Cancer Drug: ATP128 Drug: BI 754091 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 4 cohorts
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Multicenter, Non-Randomized, Dose-Confirmation and Cohort-Expansion Phase 1b Study to Evaluate the Safety, Tolerability, and Anti-Tumor Activity of ATP128, With or Without BI 754091, in Patients With Stage IV Colorectal Cancer
Actual Study Start Date : July 22, 2019
Estimated Primary Completion Date : January 15, 2021
Estimated Study Completion Date : October 15, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort 1a
6 patients with stage IV CRC having failed SoC therapies
Drug: ATP128
6 injections of ATP128

Experimental: Cohort 1b
6 patients with stage IV MSS/MMRp CRC being in SD or PR after first line of SoC (6 months duration at minimum)
Drug: ATP128
6 injections of ATP128

Drug: BI 754091
≥ 7 infusions of BI 754091

Experimental: Cohort 2a
5 patients with stage IV MSS/MMRp CRC being in SD or PR after first line of SoC (6 months duration at minimum)
Drug: ATP128
6 injections of ATP128

Drug: BI 754091
≥ 7 infusions of BI 754091

Experimental: Cohort 2b
15 patients with stage IV MSS/MMRp hepatic-limited metastatic CRC
Drug: ATP128
6 injections of ATP128

Drug: BI 754091
≥ 7 infusions of BI 754091




Primary Outcome Measures :
  1. Evaluate safety and tolerability by measure of incidence of treatment-emergent adverse events (AEs) and serious adverse events (SAEs) graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [ Time Frame: 1 year ]
    Safety


Secondary Outcome Measures :
  1. Evaluate anti-tumor effect of ATP128 alone or in combination with BI 754091 by measure of Overall Response Rate (ORR) [ Time Frame: 1 year ]
    Based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

  2. Confirm recommended phase 2 dose (RP2D) of ATP128 in combination with BI 754091 [ Time Frame: 1 year ]
    Based on evaluation of AEs with the support of pharmacodynamics

  3. Evaluate anti-tumor effect of ATP128 alone or in combination with BI 754091 by measure of Best Overall Response (BOR) [ Time Frame: 1 year ]
    Based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

  4. Evaluate anti-tumor effect of ATP128 alone or in combination with BI 754091 by measure of Duration of Response (DoR) [ Time Frame: 1 year ]
    Based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

  5. Evaluate anti-tumor effect of ATP128 alone or in combination with BI 754091 by measure of Progression Free Survival (PFS) [ Time Frame: 1 year ]
    Based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

  6. Evaluate anti-tumor effect of ATP128 alone or in combination with BI 754091 by measure of Relapse Free Survival (RFS) [ Time Frame: 1 year ]
    Based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1


Other Outcome Measures:
  1. Evaluate the humoral and cellular immune response of ATP128 alone or in combination with BI 754091 by analyses performed on blood and tumor samples [ Time Frame: 4.5 months ]
    Immune-monitoring based on the analyse of antigen specificity of humoral and cellular immune response from serum, peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs)

  2. Detect an early signal of relapse in Cohort 2b patients by liquid biopsy assay [ Time Frame: 1 year ]
    Based on ctDNA detection in the plasma



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

Inclusion Criteria:

Cohort 1a

  1. Ability to comprehend and willingness to provide written informed consent (ICF) for the study.
  2. Age ≥ 18 years.
  3. Patient with histologically or cytologically confirmed stage IV CRC who has failed standard therapies.
  4. Must have received Standard of Care systemic treatment consisting of fluoropyrimidin- oxaliplatin and/or irinotecan based therapy for stage IV CRC disease.
  5. Presence of at least 1 measurable lesion by computed tomography or magnetic resonance imaging per RECIST v1.1 as determined by the local site investigator/radiologist assessment.
  6. Presence of at least one liver lesion amenable to repeated biopsy, ideally not the one being used for measuring.
  7. Willingness to undergo two fresh liver biopsies (pre-treatment and on-treatment).
  8. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 (see Appendix 1).
  9. Life expectancy of at least 3 months.
  10. Resolution of all toxicities and any toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia). Patients with ≤ Grade 2 neuropathy and Grade ≤ 2 fatigue are an exception and may enroll.
  11. Adequate renal, hepatic, and hematologic functions as defined by laboratory parameters ≤ 7 days before study treatment initiation.
  12. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L.
  13. Absolute lymphocyte count ≥ 0.5 × 109/L.
  14. Platelets ≥ 100 × 109/L.
  15. Hemoglobin level ≥ 9 g/dL.
  16. Measured or calculated creatinine clearance (glomerular filtration rate can also be used in place of creatinine clearance) ≥ 50 mL/min according to the formula of Cockcroft-Gault (see Appendix 6).
  17. Total bilirubin ≤ 1.5 × upper limit of normal (ULN); if total bilirubin is > 1.5 x ULN then direct bilirubin must be ≤ 1.5 × ULN. Patients with known Gilbert's Syndrome may enroll if total bilirubin ≤ 3 × ULN.
  18. Alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≤ 2.5 × ULN or ≤ 5 x ULN in patients with hepatic involvement.
  19. A female patient is eligible to participate if she is not pregnant (see Appendix 2), not breastfeeding, and at least one of the following conditions applies:

    Not a woman of childbearing potential (WOCBP) as defined in Appendix 2. OR A WOCBP who agrees to use highly effective contraceptive methods as outlined in Appendix 2 during the treatment period and for at least 180 days after the last dose of study treatment and refrain from egg donation during this period.

  20. A male patient must agree to use a contraceptive as detailed in Appendix 2 of this protocol during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period.

Cohorts 1b, 2a:

  1. Ability to comprehend and willingness to provide written informed consent (ICF) for the study.
  2. Age ≥ 18 years.
  3. Histologically or cytologically confirmed CRC and MSS/MMR proficient status confirmed by polymerase chain reaction (PCR)/ immunohistochemistry or next generation sequencing (NGS) assay at local institution.
  4. Must have received a first line of SoC systemic therapy (physician choice) for stage IV disease and completed the therapy. They must have an ongoing partial response (PR) or a stable disease (SD) at the completion of this therapy, completion of therapy as defined by the investigator, however, with a minimum number of 6 months.

    Note: Patient may have also received prior adjuvant therapy for stage II or III colorectal cancer, however the adjuvant treatment for stage II and III will not be considered as a prior line of therapy in case of relapse more than 6 months after the end of treatment.

  5. Presence of at least 1 measurable lesion by computed tomography or magnetic resonance imaging per RECIST v1.1 as determined by the local site investigator/radiologist assessment.
  6. Presence of at least one liver lesion amenable to repeated biopsy, ideally not the one being used for measuring.
  7. Willingness to undergo two fresh liver biopsies (pre-treatment and on-treatment).
  8. ECOG performance status 0 to 2 (see Appendix 1).
  9. Life expectancy of at least 6 months.
  10. Has resolution of all toxicities and any toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia). Patients with ≤ Grade 2 neuropathy and Grade ≤ 2 fatigue are an exception and may enroll.
  11. Adequate renal, hepatic, thyroid and hematologic functions as defined by laboratory parameters ≤ 7 days before study treatment initiation.
  12. Absolute neutrophil count ≥ 1.5 × 109/L.
  13. Absolute lymphocyte count ≥ 0.5 × 109/L.
  14. Platelets ≥ 100 × 109/L.
  15. Hemoglobin level ≥ 9 g/dL.
  16. Measured or calculated creatinine clearance (glomerular filtration rate can also be used in place of creatinine clearance) ≥ 50 mL/min according to the formula of Cockcroft-Gault (see Appendix 6).
  17. Total bilirubin ≤ 1.5 × ULN; if total bilirubin is > 1.5 x ULN then direct bilirubin must be ≤ 1.5 × ULN. Patients with known Gilbert's Syndrome may enroll if total bilirubin ≤ 3 × ULN.
  18. ALT/AST ≤ 2.5 × ULN or ≤ 5 × ULN in patients with hepatic involvement.
  19. A female patient is eligible to participate if she is not pregnant (see Appendix 2), not breastfeeding, and at least one of the following conditions applies:

    Not a woman of childbearing potential (WOCBP) as defined in Appendix 2. OR A WOCBP who agrees to use highly effective contraceptive methods as outlined in Appendix 2 during the treatment period and for at least 180 days after the last dose of study treatment and refrain from egg donation during this period.

  20. A male patient must agree to use a contraceptive as detailed in Appendix 2 of this protocol during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period.

Cohort 2b:

  1. Ability to comprehend and willingness to provide written informed consent (ICF) for the study.
  2. Age ≥ 18 years.
  3. Histologically or cytologically confirmed CRC and MSS/MMR proficient status confirmed by PCR/immunohistochemistry or NGS assay at local institution.
  4. Radiological evidence (CT/MRI) of liver-limited stage IV CRC.
  5. Must have received first line neoadjuvant SoC systemic therapy (physician choice) for stage IV disease. May have received up to 12 weeks of this systemic SoC therapy.

    Note: Patient may have also received prior adjuvant therapy for stage II or III colorectal cancer, however the adjuvant treatment for stage II and III will not be considered as a prior line of therapy in case of relapse more than 6 months after the end of treatment.

  6. Absence of disease progression following neoadjuvant chemotherapy.
  7. Eligible for en bloc surgery with curative intent.
  8. ECOG performance status 0 to 2 (see Appendix 1).
  9. Life expectancy of at least 12 months.
  10. Adequate renal, hepatic, thyroid and hematologic functions as defined by laboratory parameters ≤ 7 days before study treatment initiation.
  11. Absolute neutrophil count ≥ 1.5 × 109 /L.
  12. Absolute lymphocyte count ≥ 0.5 × 109 /L.
  13. Platelets ≥ 100 × 109/L.
  14. Hemoglobin level ≥ 9 g/dL.
  15. Measured or calculated creatinine clearance (glomerular filtration rate can also be used in place of creatinine clearance) ≥ 50 mL/min according to the formula of Cockcroft-Gault (see Appendix 6).
  16. Total bilirubin ≤ 1.5 × ULN; if total bilirubin is > 1.5 x ULN then direct bilirubin must be ≤ 1.5 × ULN. Patients with known Gilbert's Syndrome may enroll if total bilirubin ≤ 3 × ULN.
  17. ALT/AST ≤ 2.5 × ULN or ≤ 5 × ULN in patients with hepatic involvement.
  18. A female patient is eligible to participate if she is not pregnant (see Appendix 2), not breastfeeding, and at least one of the following conditions applies:

    Not a woman of childbearing potential (WOCBP) as defined in Appendix 2. OR A WOCBP who agrees to use highly effective contraceptive methods as outlined in Appendix 2 during the treatment period and for at least 180 days after the last dose of study treatment and refrain from egg donation during this period.

  19. A male patient must agree to use a contraceptive as detailed in Appendix 2 of this protocol during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period.

Exclusion Criteria:

All Cohorts:

  1. Unwilling or unable to follow protocol requirements or to give informed consent.
  2. Gastro-intestinal bowel obstruction (partial or complete).
  3. Participation in any other study with an investigational study drug or device requires Medical Monitor approval.
  4. Prior monoclonal antibody within 4 weeks or 5 half-lives (whichever is shorter) before administration of study treatment with the exception of bevacizumab (Avastin®) which may have been received within 15 days from initiation of study treatment.
  5. Prior therapy with checkpoint inhibitors (anti-programmed death 1 (anti-PD-1), anti-programmed death-ligand 1 (anti-PD-L1), anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4)). Patients must not have received any investigational immunotherapy neither.
  6. Prior chemotherapy or targeted small molecule therapy within 15 days from initiation of study treatment.
  7. Prior radiotherapy within 2 weeks of enrolment or within 4 weeks of enrolment in the case of radiation to central nervous system (CNS), which requires ≥ 4-week washout. Patients must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
  8. Major (according the Investigator's judgment) surgery within 12 weeks before enrolment.
  9. Known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 2 years of study entry with the exception of cured basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, ductal or lobular carcinoma in situ of the breast, or other non-invasive or indolent malignancy, or cancers from which the patient has been disease-free for > 1 year, after treatment with curative intent.
  10. Immunosuppression including the continued use of systemic (at prednisone dose equivalent of > 10 mg) or topical steroids at or near the injection site (excluding inhaled and eye drop-containing corticosteroids) or the use of immunosuppressive agents for any concurrent condition. All other corticosteroids must be discontinued > 4 weeks prior to first study treatment administration.
  11. Previous vaccination (either therapeutic and/or prophylactic) against mCRC.
  12. Pregnant/nursing women or unwilling to comply with acceptable contraceptive methods during study course.
  13. History of autoimmune disease including any active autoimmune disease except vitiligo or childhood asthma.
  14. Dermatological disease requiring local immunosuppressive agent.
  15. Chronic or concurrent active infectious disease requiring systemic antibodies, antifungal, or antiviral treatment.
  16. Known medical history of human immunodeficiency virus (HIV) infection or known medical history of acquired immunodeficiency syndrome (AIDS). HIV testing is not required unless mandated by the local health authority.
  17. Has known history of or is positive for hepatitis B (hepatitis B virus surface antigen [HBsAg] reactive) or hepatitis C (HCV RNA).

    Note: Testing must be performed to determine eligibility. - Hepatitis B virus DNA must be undetectable and HBsAg negative at screening visit. - Hepatitis C antibody testing is allowed for screening purposes in countries where HCV RNA is not part of standard of care. In these cases, HCV antibody positive patients will be excluded. - Patients who have had definitive treatment for HCV are permitted if HCV RNA is undetectable at screening visit.

  18. Known active CNS metastasis and/or carcinomatous meningitis.
  19. Known cerebral oedema.
  20. Live vaccine received within 30 days before initiation of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, 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 (FluMist®) are live attenuated vaccines and are not allowed.
  21. History of allergy or hypersensitivity to any of the study drugs or study drug components.
  22. Any condition in the judgment of the Investigator which makes the patient unsuitable for trial participation.

    Cohorts 1b, 2a, 2b:

  23. Has received more than 1 line of therapy for stage IV disease (neoadjuvant therapy in Cohort 2b counts as 1 line).
  24. History of pneumonitis within the last 5 years.
  25. Active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic steroids and/or whose pulse oximetry is less than 92% "on room air".
  26. Any of the following cardiac criteria:

    • Mean resting corrected QT interval (QTc) > 470 msec.
    • Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block.
    • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years old, or any concomitant medication known to prolong the QT interval (according to institutional guidelines).
    • Ejection fraction (EF) < 55% or the lower limit of normal of the institutional standard will be excluded. Only in cases where the Investigator (or the treating physician or both) suspects cardiac disease with negative effect on the EF will the EF be measured during screening using an appropriate method according to local standards to confirm eligibility (e.g. echocardiogram [ECHO], multi-gated acquisition scan [MUGA]. A historic measurement of EF no older than 6 months prior to first study treatment administration can be accepted provided that there is clinical evidence that the EF value has not worsened since this measurement in the opinion of the Investigator or the treating physician or both.

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 ClinicalTrials.gov identifier (NCT number): NCT04046445


Contacts
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Contact: Delphine Gani +41 22 379 46 46 delphine.gani@amaltherapeutics.com
Contact: Laurence de Schoulepnikoff + 41 22 379 46 45 laurence.deschoulepnikoff@amaltherapeutics.com

Locations
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United States, Arizona
Honor Health Institute Recruiting
Scottsdale, Arizona, United States, 85258
Contact: Joyce Schaffer    480-323-1791    clinicaltrials@HonorHealth.com   
Principal Investigator: Sunil Sharma         
United States, California
University of Southern California Recruiting
Los Angeles, California, United States, 90033
Contact: Xiomara Menendez       Xiomara.Menendez@med.usc.edu   
Principal Investigator: Heinz-Josef Lenz         
United States, Texas
University of Texas, MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Edmund Scott Kopetz    713-792-2828    SKopetz@mdanderson.org   
Principal Investigator: Edmund Scott Kopetz         
Belgium
University Hospital Antwerpen Not yet recruiting
Edegem, Belgium, 2650
Contact: Hans Prenen       Hans.Prenen@uza.be   
Principal Investigator: Hans Prenen         
University Hospital Leuven Not yet recruiting
Leuven, Belgium, 3000
Contact: Eric Van Cutsem       eric.vancutsem@uzleuven.be   
Principal Investigator: Eric Van Cutsem         
Sponsors and Collaborators
Amal Therapeutics
Boehringer Ingelheim
Investigators
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Principal Investigator: Scott Kopetz MD Anderson

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Responsible Party: Amal Therapeutics
ClinicalTrials.gov Identifier: NCT04046445     History of Changes
Other Study ID Numbers: KISIMA-01
First Posted: August 6, 2019    Key Record Dates
Last Update Posted: October 21, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Amal Therapeutics:
CRC
Colorectal Cancer
MSS
Metastatic Colorectal Cancer
Liver Metastasis Colon Cancer
Stage IV Colon Cancer
Stage IV Rectal Cancer
KISIMA-01
ATP128
BI 754091
MMRp
Additional relevant MeSH terms:
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Colorectal Neoplasms
Colonic Neoplasms
Neoplasm Metastasis
Rectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neoplastic Processes
Pathologic Processes