Clinical Trials /

Phase 1b Study to Evaluate ATP128, With or Without BI 754091, in Patients With Stage IV Colorectal Cancer

NCT04046445

Description:

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

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase 1b Study to Evaluate ATP128, With or Without BI 754091, in Patients With Stage IV Colorectal Cancer
  • 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

Clinical Trial IDs

  • ORG STUDY ID: KISIMA-01
  • NCT ID: NCT04046445

Conditions

  • Colorectal Cancer
  • MSS
  • Stage IV Colon Cancer
  • Stage IV Rectal Cancer
  • Metastatic Colorectal Cancer
  • Liver Metastasis Colon Cancer

Interventions

DrugSynonymsArms
ATP128Cohort 1a
BI 754091Cohort 1b

Purpose

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

Trial Arms

NameTypeDescriptionInterventions
Cohort 1aExperimental6 patients with stage IV CRC having failed SoC therapies
  • ATP128
Cohort 1bExperimental6 patients with stage IV MSS/MMRp CRC being in SD or PR after first line of SoC (6 months duration at minimum)
  • ATP128
  • BI 754091
Cohort 2aExperimental5 patients with stage IV MSS/MMRp CRC being in SD or PR after first line of SoC (6 months duration at minimum)
  • ATP128
  • BI 754091
Cohort 2bExperimental15 patients with stage IV MSS/MMRp hepatic-limited metastatic CRC
  • ATP128
  • BI 754091

Eligibility 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 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.

         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.

         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.

         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:

          1. Has received more than 1 line of therapy for stage IV disease (neoadjuvant therapy in
             Cohort 2b counts as 1 line).

          2. History of pneumonitis within the last 5 years.

          3. 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".

          4. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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 Issue:
Description:Safety

Secondary Outcome Measures

Measure:Evaluate anti-tumor effect of ATP128 alone or in combination with BI 754091 by measure of Overall Response Rate (ORR)
Time Frame:1 year
Safety Issue:
Description:Based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Measure:Confirm recommended phase 2 dose (RP2D) of ATP128 in combination with BI 754091
Time Frame:1 year
Safety Issue:
Description:Based on evaluation of AEs with the support of pharmacodynamics
Measure:Evaluate anti-tumor effect of ATP128 alone or in combination with BI 754091 by measure of Best Overall Response (BOR)
Time Frame:1 year
Safety Issue:
Description:Based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Measure:Evaluate anti-tumor effect of ATP128 alone or in combination with BI 754091 by measure of Duration of Response (DoR)
Time Frame:1 year
Safety Issue:
Description:Based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Measure:Evaluate anti-tumor effect of ATP128 alone or in combination with BI 754091 by measure of Progression Free Survival (PFS)
Time Frame:1 year
Safety Issue:
Description:Based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Measure:Evaluate anti-tumor effect of ATP128 alone or in combination with BI 754091 by measure of Relapse Free Survival (RFS)
Time Frame:1 year
Safety Issue:
Description:Based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Amal Therapeutics

Trial Keywords

  • 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

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