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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT05440864




Registration number
NCT05440864
Ethics application status
Date submitted
21/06/2022
Date registered
1/07/2022
Date last updated
15/05/2023

Titles & IDs
Public title
Durvalumab and Tremelimumab in Resectable HCC
Scientific title
Perioperative Therapy With Durvalumab Plus Tremelimumab for Patients With Resectable Hepatocellular Carcinoma (HCC) - A Phase II Trial (NEOTOMA)
Secondary ID [1] 0 0
22-5353
Universal Trial Number (UTN)
Trial acronym
(NEOTOMA)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hepatocellular Carcinoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Non melanoma skin cancer
Cancer 0 0 0 0
Kidney
Cancer 0 0 0 0
Liver

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Tremelimumab

Experimental: Tremelimumab in combination with Durvalumab preoperatively, followed by adjuvant Durvalumab - Patients will receive 1 dose Tremelimumab (300 mg) with Durvalumab (1500mg) at cycle 1 (4W) and 1 further cycle of Durvalumab (1500mg) pre surgical resection. Post-surgical resection patients will begin adjuvant Durvalumab (1500mg Q4W) to complete 13 cycles of treatment (or 11 post operatively) in total.


Treatment: Drugs: Tremelimumab
Pre-operatively Tremelimumab will be administered first for 1 hour; the Durvalumab infusion (1hr) will start approximately 1 hour (maximum 2 hours) after the end of the Tremelimumab infusion. Post-operatively patients will receive Durvalumab Q4W to complete up to 12 months of treatment or a maximum of 11 cycles of adjuvant Durvalumab
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of greater than grade 3 adverse events (AEs) or immune related adverse events that leads to treatment cessation
Timepoint [1] 0 0
4 years
Secondary outcome [1] 0 0
Number of patients who experience a surgical delay due to treatment related adverse events (TRAEs)
Timepoint [1] 0 0
4 years
Secondary outcome [2] 0 0
Overall response rate (ORR)
Timepoint [2] 0 0
2 year
Secondary outcome [3] 0 0
Pathological response rate
Timepoint [3] 0 0
2 year
Secondary outcome [4] 0 0
Rates of R0 resection
Timepoint [4] 0 0
2 year

Eligibility
Key inclusion criteria
For inclusion in the study, patients should fulfil the following criteria at time of study
enrolment or when indicated:

1. Patient must be capable of providing written informed consent.

2. Age >18 years at time of study entry

3. Histologically proven resectable HCC (early and intermediate stage HCC)*

4. Must consent to provide biopsy sample prior to treatment

5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1

6. Childs Pugh score of 5 or 6

7. ALBI grade 1†

8. Patients with HBV infection, which is characterized by positive hepatitis B surface
antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV
DNA (=10 IU/ml or above the limit of detection per local lab standard), must be
treated with antiviral therapy, as per institutional practice, to ensure adequate
viral suppression (HBV DNA =2000 IU/mL) prior to study entry. Patients must remain on
antiviral therapy for the study duration and for 6 months after the last dose of study
medication. Patients who test positive for anti-hepatitis B core (HBc) with
undetectable HBV DNA (<10 IU/ml or under limit of detection per local lab standard) do
not require anti-viral therapy prior to study entry. These subjects will be tested at
every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is
detected (=10 IU/ml or above the limit of detection per local lab standard). HBV DNA
detectable subjects must initiate and remain on antiviral therapy for the study
duration and for 6 months after the last dose of study medication.

9. Patients with HCV infection must have management of this disease per local
institutional practice throughout the study. HCV diagnosis is characterized by the
presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody upon
enrollment.

10. Evidence of post-menopausal status or negative serum pregnancy test for female
pre-menopausal patients.

11. Female of childbearing potential and non-sterilized male partners of a female patient
of childbearing potential must agree to use effective method of contraception from the
time of screening throughout the total duration of the drug treatment and 6 months
after the last dose of study treatment. (See exclusion #22 for definition of effective
method of contraception).

12. Adequate normal organ and marrow function as defined below within screening period:

- Haemoglobin =9.0 g/dL

- Absolute neutrophil count (ANC =1.0 × 109 /L)

- Platelet count =65 × 109/L

- Serum bilirubin =1.5 x institutional upper limit of normal (ULN). <<This will not
apply to patients with confirmed Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis
or hepatic pathology), who will be allowed only in consultation with their
physician.

- AST (SGOT)/ALT (SGPT) =2.5 x institutional upper limit of normal

- Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine clearance
CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by
24-hour urine collection for determination of creatinine clearance:

Males:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) / 72 x serum creatinine (mg/dL)

Females:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 / 72 x serum creatinine
(mg/dL)

- Albumin =2.8g/dl

- International normalized ratio =1. (for patients receiving Warfarin, please consult
with the study physician)

13. Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.

14. Body weight > 30kg
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- 1. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.

2. Any prior therapy for HCC - except liver resection or ablation on one occasion only
which was given with curative intent and that occurred at least two years prior to
study enrolment.

3. Evidence of distant metastasis co-existing malignant disease or macrovascular
invasion on baseline imaging.

4. History of hepatic encephalopathy within 12 months prior to enrolment or
requirement for medications to prevent or control encephalopathy (no lactulose,
rifaximin, etc, if used for purposes of hepatic encephalopathy).

5. Evidence of portal vein thrombosis, visible on baseline/eligibility imaging, and
patients with Vp1, Vp2, Vp3 and Vp4.

6. Clinically meaningful ascites, defined as ascites requiring non-pharmacologic
intervention (eg, paracentesis) to maintain symptomatic control, within 6 months prior
to the first dose of study treatment.

(a) Patients with ascites who have required pharmacologic intervention (eg, diuretics)
and who have been on stable doses of diuretics for ascites for =2 months before
enrolment are eligible.

7. Any history of nephrotic or nephritic syndrome. 8. Evidence of symptomatic
congestive heart failure (New York Heart Association II to IV) or symptomatic or
poorly controlled cardiac arrhythmia.

9. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [except
for diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener
syndrome [e.g., granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, and uveitis]). The following are exceptions to this
criterion:

(a) Patients with vitiligo or alopecia (b) Patients with hypothyroidism (e.g.,
following Hashimoto syndrome), stable on hormone replacement (c) Any chronic skin
condition that does not require systemic therapy (d) Patients without active disease
in the last 5 years may be included but only after consultation with the Study
Physician (e) Patients with celiac disease controlled by diet alone 10. Uncontrolled
intercurrent illness, including but not limited to, ongoing or active infection,
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina
pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease (ILD),
serious chronic GI conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirements, substantially increase
the risk of incurring AEs or compromise the ability of the patient to give written
informed consent.

11. History of another primary malignancy except for the following:

1. Prostate cancer of pathologic stage less than or equal to T2cN0M0 determined from
a prior prostatectomy without biochemical recurrence and who, in the opinion of
the Investigator, are not deemed to require active intervention, or patients with
incidental histologic findings of prostate cancer that has not been treated prior
to the study and who do not require specific therapy for prostate cancer beyond
the surgery described in the Clinical Study Protocol and also are considered to
be at low risk for recurrence per the Investigator

2. Malignancy treated with curative intent and with no known active disease =5 years
before the first dose of study treatment and of low potential risk for recurrence

3. Adequately treated non-melanoma skin cancer or lentigo malignant without evidence
of disease

4. Adequately treated carcinoma in situ without evidence of disease 12. Any
concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
Concurrent use of hormonal therapy for non-cancer-related conditions (e.g.,
hormone replacement therapy) is acceptable.

13. Active infection, including tuberculosis (clinical evaluation that includes
clinical history, physical examination and radiographic findings, and
tuberculosis testing in line with local practice) or human immunodeficiency virus
(HIV; positive for HIV 1/2 antibodies).

14. Active co-infection with both HBV and HCV, or co-infected with HBV and
hepatitis D virus.

15. Known allergy or hypersensitivity to any of the study treatments or any of
the study treatment excipients.

16. Major surgery (as defined by the Investigator) within 28 days prior to
enrolment, or central venous access device placement within 7 days prior to
enrolment (biopsy from any type of surgery within 28 days is not an exclusion
criteria, nor are procedures to treat varices).

17. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF)
=470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart) 18. History
of active primary immunodeficiency 19. History of allogeneic organ
transplantation or those who are on a waiting list for liver transplantation.

20. Receipt of live attenuated vaccine within 30 days prior to the first dose of
study treatment. Note: Patients, if enrolled, should not receive live vaccine
while receiving study treatment and up to 90 days after the last dose of study
treatment.

21. Current or prior use of immunosuppressive medication within 14 days before
the first dose of study treatment. The following are exceptions to this
criterion:

(a) Intranasal, inhalational, topical steroids, or local steroid injections (e.g.,
intra-articular injection) (b) Systemic corticosteroids at physiologic doses not to
exceed 10 mg/day of prednisone or its equivalent (c) Steroids as pre-medication for
hypersensitivity reactions (e.g., CT-scan premedication) 22. Female patients who are
pregnant or breastfeeding or male or female patients of reproductive potential who are
not willing to employ highly effective birth control from screening to 6 months after
the last dose of study treatment. Not engaging in sexual activity, per the patient's
preferred and usual lifestyle, for the total duration of the treatment and 6 months
after the last dose of study treatment is an acceptable practice.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
1/08/2023
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/11/2026
Actual
Sample size
Target
28
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
Canada
State/province [1] 0 0
Ontario
Country [2] 0 0
Italy
State/province [2] 0 0
Milan
Country [3] 0 0
Spain
State/province [3] 0 0
Pamplona

Funding & Sponsors
Primary sponsor type
Other
Name
University Health Network, Toronto
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Clinica Universidad de Navarra, Universidad de Navarra
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
University of Milan
Address [2] 0 0
Country [2] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Hepatocellular Carcinoma (HCC) is the third most common cause of death from cancer world wide
and the incidence is rising globally. Despite surgical resection in appropriate patients,
many patients recur.

The results of the IMbrave150 study have established PD-L1 inhibition in combination with
VEGF inhibition as a new standard of care highlighting the role of immune checkpoint
inhibition in advanced HCC. In addition, the combination of Tremelimumab and Durvalumab has
demonstrated efficacy in advanced HCC; the HIMALAYA trial has now completed accrual in
treatment naïve patients with advanced HCC. Furthermore the earlier use of immune checkpoint
inhibitors in this disease are being explored with adjuvant combination strategies, including
the EMERALD-2 trial (NCT03847428). Neoadjuvant treatment in HCC allows for delivery of
treatment pre surgery and may enhance pathological responses and improve outcomes. The
delivery of combination CTLA-4 and PD-L1 inhibition has demonstrated efficacy in other tumour
types in the neoadjuvant setting where the impact on the tumour microenvironment has also
been evaluated. The safety and feasibility of Durvalumab and Tremelimumab in resectable HCC
has yet to be established.

Hypotheses Pre-operative (pre-op) Durvalumab and Tremelimumab treatment is safe and feasible
in pre surgical setting for upfront resectable HCC The combination of Durvalumab and
Tremelimumab pre-op will result in changes in immune and molecular characteristics within the
tumour microenvironment.

Overall Study Design This is a phase II, open-label multi-centre study to assess safety of
Durvalumab and Tremelimumab treatment in pre-op setting for upfront resectable HCC, followed
by adjuvant Durvalumab.

28 patients are expected to enrol at three sites. Patients will receive pre-op: 1 dose
Tremelimumab (300mg) (T300) with Durvalumab (1500mg) at cycle 1 and 1 further cycle of
Durvalumab (1500mg) only. Post-surgical resection, adjuvant therapy will consist of
Durvalumab Q4W for up to a maximum of 12 months in total or 13 cycles of Durvalumab (11
cycles post op).

All participants will be treated until progressive disease or unacceptable toxicity or
withdrawal of consent or another discontinuation criterion is met. All participants will be
followed for survival until the end of study.

No dose reductions of Tremelimumab and Durvalumab will be allowed. Statistics The primary
objective of this study is to assess safety of pre-op treatment with Durvalumab and
Tremelimumab.

For safety, with the null proportion of patients who discontinue treatment due to AEs, imAEs
or SAE is 30% versus the alternative proportion is 10% or less than 10%, a sample size of 28
provides 80% power to detect the proportion difference with a two-sided alpha level of 0.1.

The sample size estimate is based on the two-sided exact test for binomial proportion
considering Binomial Enumeration method.
Trial website
https://clinicaltrials.gov/ct2/show/NCT05440864
Trial related presentations / publications
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Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed

Contacts
Principal investigator
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Gonzalo Sapisochin, MD
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Univeristy Health Network
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Contact person for public queries
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Claudia Sweeney
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416-634-8300
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claudia.sweeney@ozmosisresearch.ca
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Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT05440864