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

  • STATUS
    Recruiting
  • End date
    Apr 15, 2022
  • participants needed
    32
  • sponsor
    Amal Therapeutics
Updated on 13 February 2021
ct scan
cancer
absolute neutrophil count
systemic therapy
measurable disease
gilbert's syndrome
oxaliplatin
neutrophil count
immunohistochemistry
irinotecan
adjuvant therapy
neuropathy
stage iv colorectal cancer

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

Details
Condition Marinesco-Sjogren syndrome, Colorectal Cancer, Rectal disorder, Colon Cancer Screening, Rectal Disorders, Colon cancer; rectal cancer, Metastatic Colorectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer, Metastatic Colon Cancer, Liver Metastasis Colon Cancer, colorectal neoplasm, colorectal cancers, cancer, colorectal, colorectal tumor, tumors, colorectal
Treatment BI 754091, ATP128
Clinical Study IdentifierNCT04046445
SponsorAmal Therapeutics
Last Modified on13 February 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have any of these conditions: Metastatic Colorectal Cancer or Rectal Disorders or Stage IV Colon Cancer or Liver Metastasis Colon Cancer or Colorectal Cancer or Rectal disorder or ...?
Do you have any of these conditions: colorectal tumor or Rectal disorder or Colon Cancer Screening or Stage IV Colon Cancer or Metastatic Colon Cancer or Marinesco-Sjogren syndrome or Liv...?
Do you have any of these conditions: Colon Cancer Screening or Marinesco-Sjogren syndrome or Liver Metastasis Colon Cancer or colorectal neoplasm or Metastatic Colorectal Cancer or Rectal...?
Do you have any of these conditions: Liver Metastasis Colon Cancer or colorectal tumor or tumors, colorectal or Metastatic Colon Cancer or Colorectal Cancer or Metastatic Colorectal Cance...?
Do you have any of these conditions: Marinesco-Sjogren syndrome or colorectal cancers or Liver Metastasis Colon Cancer or colorectal neoplasm or Colon cancer; rectal cancer or Stage IV Co...?
Cohort 1a
Ability to comprehend and willingness to provide written informed consent (ICF) for the study
Age 18 years
Patient with histologically or cytologically confirmed stage IV CRC who has failed standard therapies
Must have received Standard of Care systemic treatment consisting of fluoropyrimidinoxaliplatin and/or irinotecan based therapy for stage IV CRC disease
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
Presence of at least one liver lesion amenable to repeated biopsy, ideally not the one being used for measuring
Willingness to undergo two fresh liver biopsies (pre-treatment and on-treatment)
Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 (see Appendix 1)
Life expectancy of at least 3 months
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
Adequate renal, hepatic, and hematologic functions as defined by laboratory parameters 7 days before study treatment initiation
Absolute neutrophil count (ANC) 1.5 109/L
Absolute lymphocyte count 0.5 109/L
Platelets 100 109/L
Hemoglobin level 9 g/dL
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)
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
Alanine aminotransferase/aspartate aminotransferase (ALT/AST) 2.5 ULN or 5 x ULN in patients with hepatic involvement
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
\. A male patient must agree to use a contraceptive as detailed in Appendix
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
Ability to comprehend and willingness to provide written informed consent (ICF) for the study
Age 18 years
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
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
months after the end of treatment
\. 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
\. Presence of at least one liver lesion amenable to repeated biopsy, ideally
not the one being used for measuring. If the investigator judges the biopsies
\. Willingness to undergo two fresh liver biopsies (pre-treatment and on-
to be a risk or an undue inconvenience for the patient health/condition, they
may be skipped (however, a minimum of 50% of patients must undergo the paired
\. ECOG performance status 0 to 2 (see Appendix 1)
biopsies)
\. Life expectancy of at least 6 months
\. Has resolution of all toxicities and any toxic effect(s) of the most
treatment). If the investigator judges the biopsies to be a risk or an undue
recent prior therapy to Grade 1 or less (except alopecia). Patients with Grade
inconvenience for the patient health/condition, they may be skipped (however
neuropathy and Grade 2 fatigue are an exception and may enroll
a minimum of 50% of patients must undergo the paired biopsies)
\. Adequate renal, hepatic, thyroid and hematologic functions as defined by
laboratory parameters 7 days before study treatment initiation
\. Absolute neutrophil count 1.5 109/L
\. Absolute lymphocyte count 0.5 109/L
\. Platelets 100 109/L
\. Hemoglobin level 9 g/dL
\. 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)
\. 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
\. ALT/AST 2.5 ULN or 5 ULN in patients with hepatic involvement
\. 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
\. A male patient must agree to use a contraceptive as detailed in Appendix
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
Ability to comprehend and willingness to provide written informed consent (ICF) for the study
Age 18 years
Histologically or cytologically confirmed CRC and MSS/MMR proficient status confirmed by PCR/immunohistochemistry or NGS assay at local institution
Radiological evidence (CT/MRI) of liver-limited stage IV CRC
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
months after the end of treatment
\. Absence of disease progression following neoadjuvant chemotherapy
\. Eligible for en bloc surgery with curative intent
\. ECOG performance status 0 to 2 (see Appendix 1)
\. Life expectancy of at least 12 months
\. Adequate renal, hepatic, thyroid and hematologic functions as defined by
laboratory parameters 7 days before study treatment initiation
\. Absolute neutrophil count 1.5 109 /L
\. Absolute lymphocyte count 0.5 109 /L
\. Platelets 100 109/L
\. Hemoglobin level 9 g/dL
\. 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)
\. 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
\. ALT/AST 2.5 ULN or 5 ULN in patients with hepatic involvement
\. 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
\. A male patient must agree to use a contraceptive as detailed in Appendix
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
Unwilling or unable to follow protocol requirements or to give informed consent
Gastro-intestinal bowel obstruction (partial or complete)
Participation in any other study with an investigational study drug or device requires Medical Monitor approval
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
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
Prior chemotherapy or targeted small molecule therapy within 15 days from initiation of study treatment
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
Major (according the Investigator's judgment) surgery within 12 weeks before enrolment
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
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
Previous vaccination (either therapeutic and/or prophylactic) against mCRC
Pregnant/nursing women or unwilling to comply with acceptable contraceptive methods during study course
History of autoimmune disease including any active autoimmune disease except vitiligo or childhood asthma
Dermatological disease requiring local immunosuppressive agent
Chronic or concurrent active infectious disease requiring systemic antibodies, antifungal, or antiviral treatment
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
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
\. Known active CNS metastasis and/or carcinomatous meningitis
\. Known cerebral oedema
\. 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-Gurin, 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
\. History of allergy or hypersensitivity to any of the study drugs or study
drug components
\. Any condition in the judgment of the Investigator which makes the patient
unsuitable for trial participation
Cohorts 1b, 2a, 2b
\. Has received more than 1 line of therapy for stage IV disease
(neoadjuvant therapy in Cohort 2b counts as 1 line)
\. History of pneumonitis within the last 5 years
\. 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
\. 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
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