Trial Title:
Pre-operative Targeted Treatments in Molecularly Selected Resectable Colorectal Cancer (UNICORN)
NCT ID:
NCT05845450
Condition:
Colorectal Cancer
Resectable Colorectal Carcinoma
Conditions: Official terms:
Colorectal Neoplasms
Trastuzumab
Durvalumab
Panitumumab
Sotorasib
Trastuzumab deruxtecan
Conditions: Keywords:
targeted treatment
molecular alterations
platform trial
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Single Group Assignment
Intervention model description:
Phase II, multicentre, single-arm, open-label, multi-cohort trial
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Trastuzumab deruxtecan
Description:
trastuzumab deruxtecan 5.4 mg/kg IV on day 1
Arm group label:
Cohort 1: HER2 positive
Intervention type:
Drug
Intervention name:
Durvalumab
Description:
durvalumab 1500 mg IV on day 1
Arm group label:
Cohort 2: POLE/D1 mutated with ultra-mutated status (>100 Mut/Megabase)
Intervention type:
Drug
Intervention name:
Panitumumab
Description:
panitumumab 6 mg/kg IV on days 1 and 15
Arm group label:
Cohort 3: EGFR-dependent
Arm group label:
Cohort 8: KRAS G12C mutated
Intervention type:
Drug
Intervention name:
Botensilimab
Description:
botensilimab 1 mg/kg on day 1
Arm group label:
Cohort 4: pMMR/MSS status
Arm group label:
Cohort 5: pMMR/MSS status
Arm group label:
Cohort 6: dMMR/MSI-H status
Arm group label:
Cohort 7: dMMR/MSI-H status
Intervention type:
Drug
Intervention name:
Balstilimab
Description:
balstilimab 3 mg/Kg on days 1 and 15
Arm group label:
Cohort 5: pMMR/MSS status
Arm group label:
Cohort 7: dMMR/MSI-H status
Intervention type:
Drug
Intervention name:
Sotorasib
Description:
sotorasib 960 mg orally once daily from day 1 to 28
Arm group label:
Cohort 8: KRAS G12C mutated
Summary:
This is a window-of-opportunity umbrella platform trial enrolling non-metastatic
resectable colorectal patients selected for the presence of a specific targetable
molecular alteration. The study aims to test the activity of specific targeted
agents/combinations given as a short-course pre-operative strategy, matched with the
specific alteration detected, followed by standard of care surgery.
Detailed description:
Patients with histologically confirmed non metastatic, radiologically staged as cT3-4
colorectal cancer eligible for radical surgery will be centrally molecularly prescreened
by means of next-generation sequencing, HER2 IHC +/- HER2 silver-in situ hybridization
and MMR proteins IHC with the aim to identify the presence of selected targetable
molecular profiles/alterations. Whenever a pre-specified molecular profile/alteration is
identified, the patient will be eligible for the matching Cohort and, after enrollment,
will receive a specific short-course preoperative targeted treatment.
A total of 14 patients will be enrolled in each pre-specified molecularly-identified
Cohort, according to the review of a Molecular Tumor Board established by the Sponsor,
that will specifically evaluate the occurring and co-occurring molecular alterations.
Cohort 1 - patients with pMMR/MSS status and HER2 overexpression/amplification will
receive the HER2 directed ADC trastuzumab deruxtecan 5.4 mg/kg IV on day 1.
Cohort 2 - patients with POLE/D1 mutation with ultra-mutated status (>100Mut/Megabase)
will receive the anti-PDL-1 monoclonal antibody durvalumab 1500 mg IV on day 1.
Cohort 3 - patients with EGFR-dependent tumor (pMMR/MSS status, RAS and BRAF wild type
status, PRESSING negative status and left-sided primary cancer) will receive the
anti-EGFR agent panitumumab 6 mg/kg IV on days 1 and 15.
Cohort 4 - patients with pMMR/MSS status and absence of HER2
overexpression/amplification, absence of POLE/D1 proof-read domain pathogenic mutation
associated with ultra-mutated status will receive the anti-CTLA4 antibody botensilimab 1
mg/kg on day 1.
Cohort 5 (will be opened sequentially, after completion of Cohort 4) - patients with
pMMR/MSS status and absence of HER2 overexpression/amplification, absence of POLE/D1
proof-read domain pathogenic mutation associated with ultra-mutated status will receive
the anti-CTLA4 antibody botensilimab 1 mg/kg on day 1 plus the anti-PD-1 balstilimab 3
mg/Kg on days 1 and 15.
Cohort 6 - patients with dMMR/MSI-H status and absence of POLE/D1 proof-read domain
pathogenic mutation associated with ultra-mutated status will receive the anti-CTLA4
antibody botensilimab 1 mg/kg on day 1.
Cohort 7 (will be opened sequentially, after completion of Cohort 6) - patients with
dMMR/MSI-H status and absence of POLE/D1 proof-read domain pathogenic mutation associated
with ultra-mutated status will receive the anti-CTLA4 antibody botensilimab 1 mg/kg on
day 1 plus the anti-PD-1 balstilimab 3 mg/Kg on days 1 and 15.
Cohort 8 - patients with pMMR/MSS status and KRAS G12C mutation will receive the KRAS
G12C inhibitor sotorasib 960 mg orally once daily from day 1 to 28 plus the anti-EGFR
inhibitor panitumumab 6 mg/kg IV on days 1 and 15.
After receiving the pre-specified study treatment, patients will be submitted to radical
surgery at day 35 +/- 5 days. After surgery, patients will receive standard adjuvant
chemotherapy as per national and international guidelines and according to the suggestion
of a central multidisciplinary team. Then, standard follow up will be started as per
local guidelines. Baseline assessments include radiological imaging (chest-abdomen-pelvis
CT scan with contrast or abdomen MRI with contrast plus thorax CT without contrast if
indicated, pelvis MRI mandatory for rectal cancer, and 18-FDG-PET scan if clinically
indicated). Tumor re-assessments will be performed immediately prior to surgery at week
4-5. Safety assessments include monitoring of adverse events, clinical laboratory tests
(chemistry, hematology, coagulation and urinalysis), vital signs, physical examinations
and ECG as applicable.
Health-care related quality of life analysis will be done thanks to the administration of
patient-reported outcomes questionnaires (EORTC QLQ-C30, EORTC QLQ-CR29, Euro QoL
EQ-5D-5L) at baseline, during pre-operative treatment and at restaging.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
General inclusion criteria
- Provide a signed and dated informed consent document.
- Age ≥ 18 years at time of informed consent.
- ECOG PS of 0 and 1.
- Histologically confirmed colorectal cancer adenocarcinoma that is judged as
initially resectable with elective surgery aimed at radical intent with R0 margins
as per multidisciplinary team assessment.
- Radiological stage cT3-4, N0-2, M0 using computed tomography (CT) as in the pivotal
FOxTROT study.
- Patients with rectal cancer candidate for R0 resection, not requiring pre-operative
radiotherapy based on multidisciplinary team assessment, with the following
characteristics on high-resolution thin slice (3 mm) contrast-enhanced magnetic
resonance imaging (MRI):
- ≤ T3a defined at the MRI (perivisceral fat infiltration <2 mm) and clinical N0
- Upper-medium, defined as tumors with distal margin ≥ 5 cm from the anal verge.
- Absence of mesorectal fascia invasion, as defined as a distance ≥ 1 mm between
tumor and the mesorectal fascia.
- Able to provide enough archival FFPE tumor specimen that is already available from
initial diagnostic procedures for the purpose of molecular pre-screening.
- Presence of one of the selected molecular profile/alteration after central
pre-screening and necessary for the assignment to a matching treatment cohort.
- No prior systemic treatment for colorectal cancer or neoadjuvant radiation therapy
for rectal cancer.
- Adequate bone marrow function (absolute neutrophil count ≥ 1.5 × 109/L; platelet
count ≥ 100 × 109/L; hemoglobin ≥ 9.0 g/dL)
- Adequate renal function characterized by serum creatinine ≤ 1.5 × upper limit of
normal (ULN) or calculated by Cockroft-Gault formula or directly measured creatinine
clearance ≥ 50 mL/min at screening.
- Adequate hepatic function (serum total bilirubin ≤ 1.5 × ULN and < 2 mg/dL. Note:
Patients who have a total bilirubin level 1.5 × ULN will be allowed if their
indirect bilirubin level is ≤ 1.5 × ULN; Alanine aminotransferase and/or aspartate
aminotransferase ≤ 2.5 × ULN).
- Women of childbearing potential must have a negative blood pregnancy test at the
baseline visit. For this trial, women of childbearing potential are defined as all
women after puberty, unless they are postmenopausal for at least 12 months, are
surgically sterile, or are sexually inactive. A postmenopausal state is defined as
no menses for 12 months without an alternative medical cause. A high follicle
stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a
post-menopausal state in women not using hormonal contraception or hormonal
replacement therapy. However, in the absence of 12 months of amenorrhea, a single
FSH measurement is insufficient.
- Subjects and their partners must be willing to avoid pregnancy during the trial and
until a specific time interval after the last trial treatment: 7 months for female
and 4 for male patients after last dose of trastuzumab-deruxtecan, 3 months for
durvalumab, botensilimab and balstilimab and 2 months for panitumumab. Male subjects
with female partners of childbearing potential and female subjects of childbearing
potential must, therefore, be willing to use adequate contraception as approved by
the Investigator (barrier contraceptive measure or oral contraception).
- Willing and able to comply with scheduled visits, treatment plan, laboratory tests
and other study procedures.
Specific inclusion criteria for each Cohort
COHORT 1: pMMR/MSS status and HER2-positive status and LVEF ≥ 50% within 28 days before
enrolment, international normalised ratio or Prothrombin time and either partial
thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN
COHORT 2: Proofread domain mutations in POLE or POLD1 associated with ultra-mutated
status, i.e. tumor mutational burden >100 Mut/Mb.
COHORT 3: pMMR/MSS status and wild-type status for RAS and BRAF, absence of molecular
predictors of resistance (PRESSING panel negative), Left-sided and rectal primary tumor
location, according to the specific inclusion criterion regarding rectal tumors.
COHORT 4: pMMR/MSS status and absence of HER2 overexpression/amplification, absence of
POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status and
absence of KRAS G12C mutation.
COHORT 5: pMMR/MSS status and absence of of HER2 overexpression/amplification, absence of
POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status.
COHORT 6: dMMR/MSI-H status and absence of POLE/D1 proof-read domain pathogenic mutation
associated with ultra-mutated status.
COHORT 7: dMMR/MSI-H status and absence of POLE/D1 proof-read domain pathogenic mutation
associated with ultra-mutated status.
COHORT 8: pMMR/MSS status and KRAS G12C mutation, absence of HER2
overexpression/amplification and wild-type status for BRAF.
Exclusion Criteria:
General exclusion criteria
- Distant metastases at any site, as defined by negativity of chest/abdomen/pelvis
contrast-enhanced computed tomography (CT).
- Risk criteria for obstructing disease at radiology or endoscopy as defined in the
pivotal FOxTROT study.
- Need to receive neoadjuvant radiation or chemoradiation in patients with rectal
cancer.
- Patients with known hypersensitivity to the study drug of the assigned cohort or to
its excipients or to drugs belonging to the same drug class.
- Previous or concurrent malignancy within 2 years of study entry.
- Impaired cardiovascular function or clinically significant cardiovascular diseases,
including any of the following: history of acute myocardial infarction, acute
coronary syndromes (including unstable angina, coronary artery bypass graft,
coronary angioplasty or stenting) ≤ 6 months prior to start of study treatment;
symptomatic congestive heart failure (i.e., Grade 2 or higher), history or current
evidence of clinically significant cardiac arrhythmia and/or conduction abnormality
≤ 6 months prior to start of study treatment, except atrial fibrillation and
paroxysmal supraventricular tachycardia.
- Known history of HIV infection.
- Active infection including tuberculosis, hepatitis B, hepatitis C. Patients with a
past or resolved HBV infection (defined as the presence of hepatitis B core antibody
[anti-HBc] and absence of HBsAg) are eligible only in case of negativity of HBV DNA.
Patients positive for hepatitis C (HCV) antibody are eligible only if PCR is
negative for HCV RNA.
- Other severe acute or chronic diseases that may increase the risk associated with
study participation or study drug administration or that may interfere with the
interpretation of study results and, in the judgment of the Investigator, would make
the patient an inappropriate candidate for the study.
- Any psychiatric condition that would prohibit the understanding or rendering of
informed consent and that would limit compliance with trial requirements.
- Women in pregnancy or lactation condition. Women with child-bearing potential or
sexually-active men not willing to use adequate contraception during whole study
period.
- Use of any disallowed drugs.
Specific exclusion criteria for each Cohort:
COHORT 1:
- Previous treatment with a DXd-containing ADC or any anti-HER2 agent.
- Has LVEF< 50% within 28 days before enrolment.
- Has a history of (non-infectious) ILD/pneumonitis that required steroids, has
current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by
imaging at Screening. (eg, pulmonary emboli within 3 months of the enrolment, severe
asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung
disease, pleural effusion, etc.).
- Lung-specific intercurrent clinically significant illnesses including, but not
limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months
of the enrolment, severe asthma, severe chronic obstructive pulmonary disease
[COPD], restrictive lung disease, pleural effusion, etc.).
- Any autoimmune, connective tissue, or inflammatory disorders where there is
documented, or a suspicion of, pulmonary involvement at the time of Screening.
- Prior pneumonectomy.
- Has substance abuse or any other medical conditions that may interfere with the
subject's participation in the clinical study or evaluation of the clinical study
results.
- Patients with a medical history of myocardial infarction within 6 months before
randomization/enrolment, symptomatic congestive heart failure (CHF) (New York Heart
Association Class II to IV), subjects with troponin levels above ULN at screening
(as defined by the manufacturer), and without any myocardial related symptoms,
should have a cardiologic consultation before enrollment to rule out myocardial
infarction.
- Corrected QT interval (QTcF) prolongation to > 470 msec (females) or >450 msec
(males) based on average of the screening triplicate12-lead ECG.
- A pleural effusion, ascites or pericardial effusion that requires drainage,
peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).
COHORT 2, 4, 5, 6, 7:
- History of autoimmune diseases or history of bone marrow or organ transplantation
that requires immunosuppressive therapy.
- History of active primary immunodeficiency.
- Any condition requiring systemic treatment with corticosteroids at doses equal or
superior to 10 mg daily of prednisone or equivalents, or other immunosuppressive
drugs within 14 days from the inclusion in the study.
- Administration of live vaccines within 4 weeks from the inclusion in the study.
Note: patients, if enrolled, should not receive live vaccine while receiving study
drug(s) and up to 30 days after the last dose of study drug(s).
- Prior treatment with anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibody or
pathway-targeting agents.
COHORT 3 and 8
- History of interstitial lung disease (e.g. pneumonitis or pulmonary fibrosis) or
evidence of interstitial lung disease on baseline chest CT scan.
- Magnesium below the LNL.
- Prior treatment with an EGFR inhibitor.
COHORT 8:
- Patients who are unable to take a drug by mouth or previous clinical conditions or
surgical resection that may affect the absorption of the study drug.
- Use of CYP3A4 or P-gp substrates with a narrow therapeutic window within 14 days or
5 half-lives of the drug or its major active metabolite, whichever is longer.
- Use of any herbal medications/supplements.
- Tumors with KRAS, NRAS, HRAS, BRAF or PTPN11 (SHP2) mutations, except KRAS G12C.
- Prior treatment with a KRAS G12C inhibitor.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
Address:
City:
Milan
Zip:
20133
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Filippo Pietrantonio, MD
Phone:
+39 0223903807
Email:
filippo.pietrantonio@istitutotumori.mi.it
Contact backup:
Last name:
Federica Palermo
Phone:
+39 0223903835
Email:
unicornstudy@istitutotumori.mi.it
Start date:
May 11, 2023
Completion date:
May 2028
Lead sponsor:
Agency:
Gruppo Oncologico del Nord-Ovest
Agency class:
Other
Source:
Gruppo Oncologico del Nord-Ovest
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05845450
