Official Title
An Early Access Program for Durvalumab and Tremelimumab as First Line Treatment for Patients With Unresectable Hepatocellular Carcinoma
Brief Summary

To provide early access (i.e., before marketing authorisation) to tremelimumab 300 mg IV administered once on Day 1 of Cycle 1 plus durvalumab 1500 mg IV followed by durvalumab 1500 mg IV Q4W monotherapy in patients with unresectable HCC.

Detailed Description

Overall design This is a multi centre, open-label, early access program (EAP) designed to
provide treatment access to intravenous (IV) combination treatment regimen of 300 mg
tremelimumab administered IV once on Day 1 of Cycle 1 plus 1500 mg durvalumab IV (MEDI 4736)
followed by durvalumab IV monotherapy administered once every 4 weeks (Q4W) for eligible
patients with unresectable, hepatocellular carcinoma (HCC).

Durvalumab and tremelimumab will be provided free of charge to the patients entering this
program.

This global EAP will be opened in a staggered fashion, country by country, based on the
requesting Treating Physician(s) and local regulations, ending when durvalumab and
tremelimumab has received marketing authorisation in first line treatment in patients with
unresectable hepatocellular carcinoma.

Target patient population Patients with unresectable HCC and Barcelona Clinic Liver Cancer
(BCLC) stage B (who are not eligible or no longer suitable for locoregional therapy [LRT]) or
stage C before entering the EAP.

Program period The EAP will enrol patients and provide resupply of durvalumab and
tremelimumab until durvalumab and tremelimumab has received marketing authorisation in first
line treatment for patients with unresectable HCC as per local regulations.

The EAP will be closed to new patients based on local regulations or when commercially
reimbursed product is available. After reimbursement is secured, or denial of reimbursement,
or decision by the Sponsor to close the enrolment, whichever occurs first, no new patients
can be enrolled after this point.

In the event that market license approval or reimbursement should not be granted,
contingencies will be made to ensure continued drug supply for patients who are still
deriving benefit from durvalumab and tremelimumab.

Number of patients:

The number of patients who will enrol in the EAP is based on approval of unsolicited requests
received from the Treating Physician.

Program treatment:

On Day 1 of Cycle 1, tremelimumab will be administered first followed by durvalumab 1 hour
later. Tremelimumab will be given once on Day 1 of Cycle 1. Durvalumab monotherapy is then
given Q4W.

Duration of treatment:

Patients may continue to receive EAP treatment providing they continue to show clinical
benefit, as judged by the Treating Physician, in the absence of unacceptable safety concerns
until disease progression, toxicity or withdrawal.

Approved for marketing
Intermediate-size Population
Unresectable Hepatocellular Carcinoma

Drug: Durvalumab

Dose: 1500mg Route: IV
Other Name: Imfinzi

Drug: Tremelimumab

Dose: 300mg Route: IV

Eligibility Criteria

Inclusion Criteria:

1. Age 18 years and over at the time of screening.

2. Body weight over 30 kg.

3. Confirmed HCC based on histopathological findings from tumour tissues.

4. Must not have received prior systemic therapy for HCC.

5. Must not be eligible for locoregional therapy for resectable HCC. For patients who
progressed after locoregional therapy for HCC, locoregional therapy must have been
completed at least 28 days before the baseline scan for the programme.

6. Barcelona Clinic Liver Cancer (BCLC) stage B (that is not eligible for locoregional
therapy) or stage C (refer to Appendix H).

7. Child-Pugh Score Class A; or Child-Pugh Class B7 or B8 at discretion of treating
physician (refer to Appendix I).

8. Patients with HBV infection, characterised by positive hepatitis B surface antigen
(HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV
deoxyribonucleic acid (DNA) (≥10 IU/mL or above the limit of detection per local or
central lab standard), must be treated with antiviral therapy, as per institutional
practice to ensure adequate viral suppression (HBV DNA <2000 IU/mL) before enrolment.
Patients must remain on antiviral therapy for the duration of their participation in
the EAP and for 6 months after the last dose of EAP medication. Patients who test
positive for anti-hepatitis B core (HBc) with undetectable HBV DNA (<10 IU/mL or under
the limit of detection per local or central lab standard) do not require anti-viral
therapy before enrolment. These participants will be tested at every cycle to monitor
HBV DNA levels and initiate anti-viral therapy if HBV DNA is detected (≥10 IU/mL or
above the limit of detection per local or central lab standard). HBV DNA detectable
patients must initiate and remain on anti-viral therapy for time they are in the EAP
and for 6 months after the last dose of EAP medication.

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

10. At least 1 measurable lesion, not previously irradiated, that can be accurately
measured at baseline ≥10 mm in the longest diameter (except lymph nodes, which must
have as short axis ≥15 mm) with computerised tomography (CT) or magnetic resonance
imaging (MRI), and that is suitable for accurate repeated measurements as per RECIST
1.1 guidelines (Eisenhauer et al, 2009). A lesion which progressed after previous
ablation or transarterial chemoembolization (TACE) could be measurable if it meets
these criteria.

11. Adequate organ and marrow function, as defined below. Criteria "a", "b", "c", and "f"
cannot be met with transfusions, infusions, or growth factor support administered
within 14 days of starting the first dose of EAP treatment.

1. Haemoglobin ≥9 g/dL

2. Absolute neutrophil count ≥1000/μL

3. Platelet count ≥75,000/μL

4. Total bilirubin (TBL) ≤2.0 x upper limit of normal (ULN)

5. AST and ALT ≤5xULN

6. Albumin ≥2.8 g/dL

7. International normalised ratio (INR) ≤1.6. Note: INR prolongation due to
anticoagulants for prophylaxis (e.g., atrial fibrillation) in patients without
liver cirrhosis could be exception.

8. Calculated creatinine clearance ≥50 mL/minute as determined by Cockcroft Gault
(using actual body weight) or 24-hour urine creatinine clearance

12. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal as described
in Section 5.3.4.

13. Must have a life expectancy of at least 12 weeks.

14. Willing and able to comply with the protocol for the duration of the EAP including
undergoing treatment and scheduled visits and examination including follow up.

15. Able to provide written informed consent and any locally-required authorisation (e.g.,
Health Insurance Portability and Accountability Act [HIPAA] in the United States [US],
European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal
representative before performing any protocol-related procedures, including screening
evaluations.

Exclusion Criteria:

Patients should not enter the EAP if any of the following exclusion criteria are fulfilled:

1. Concurrent enrolment in a clinical study unless it is an observational (non
interventional) clinical study or during the follow-up period of an interventional
study.

2. Have received an investigational product within 28 days before the first dose of EAP
treatment.

3. Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria
for Adverse Event (CTCAE) Grade ≥2 from previous anticancer therapy except alopecia,
vitiligo, and the laboratory values defined in the inclusion criteria:

- Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
consultation with the Treating Physician.

- Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab or tremelimumab may be included only after consultation
with the Treating Physician.

4. Any concurrent chemotherapy, study drug, or biologic or hormonal therapy for cancer
treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g.,
hormone replacement therapy) is acceptable.

5. Known allergy or hypersensitivity to any of the EAP treatments or any of the EAP
treatment excipients.

6. Child-Pugh Score Class B9; or Child-Pugh Class C

7. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of
radiation within 28 days of the first dose of EAP treatments.

8. Major surgical procedure (as defined by the Treating Physician) within 28 days before
the first dose of EAP treatment. Note: local surgery of isolated lesions for
palliative intent is acceptable.

9. History of allogenic organ transplantation (e.g., liver transplant).

10. History of hepatic encephalopathy within the past 12 months or requirement for
medications to prevent or control encephalopathy (e.g., no lactulose, rifaximin, etc
if used for purposes of hepatic encephalopathy.

11. Clinically meaningful ascites, defined as any ascites requiring non-pharmacologic
intervention (e.g., paracentesis) to maintain symptomatic control, within 6 months
before the first EAP treatment dose. Patients on stable doses of diuretics for ascites
for ≥2 months are eligible.

12. Patients with main portal vein thrombosis (i.e., thrombosis in the main trunk of the
portal vein, with or without blood flow) on baseline imaging.

13. Active or previously documented GI bleeding (e.g., oesophageal varices or ulcer
bleeding) within 12 months. (Note: for patients with history of GI bleeding for >12
months or assessed as high risk for oesophageal variceal by the Treating Physician,
adequate endoscopic therapy according to institutional standards is required).

14. Patient currently exhibits symptomatic or uncontrolled hypertension defined as
diastolic blood pressure >90 mmHg or systolic blood pressure >140 mmHg.

15. Any condition interfering with swallowing pills, or other contraindication to oral
therapy, or uncontrolled diarrhoea.

16. Active or previously 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 [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis,
hypophysitis, uveitis, etc]). Patients without active disease in the last 5 years are
excluded unless discussed with the Treating Physician and considered appropriate for
EAP participation. The following are exception to this criterion:

- Patients with vitiligo or alopecia

- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement

- Any chronic skin condition that does not require systemic therapy

- Patients with celiac disease controlled by diet alone

17. Patients co-infected with HBV and HCV, or co-infected with HBV and hepatitis D virus
(HDV). HBV positive (presence of HbsAg and/or anti-HBcAb with detectable HBV DNA); HCV
positive (presence of anti-HCV antibodies); HDV positive (presence of anti-HDV
antibodies).

18. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease (ILD), serious chronic
GI conditions associated with diarrhoea, inferior vena cava thrombosis, or psychiatric
illness/social situations that would limit compliance with EAP requirement,
substantially increase the risk of incurring AEs, or compromise the ability of the
patient to give written informed consent.

19. History of another primary malignancy except for:

- Malignancy treated with curative intent and with known active disease ≥5 years
before the first dose of EAP treatment and of low potential risk for recurrence

- Patients with a history of prostate cancer of stage recurrence or progression and who, in the opinion of the Treating Physician are
not deemed to require active intervention

- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease

- Adequately treated carcinoma in situ without evidence of disease

20. History of leptomeningeal carcinomatosis.

21. History of, or current, brain metastases or spinal cord compression. Patients with
suspected brain metastases at screening should have an MRI (preferred) or CT, each
preferably with IV contrast of the brain before EAP entry.

22. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.

23. History of active primary immunodeficiency.

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

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

- Intranasal, inhaled, topical steroids, or local steroid injections (e.g.,
intra-articular injection)

- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent

- Steroids as pre-medication for hypersensitivity reactions (e.g., CT scan
pre-medication)

26. Receipt of live attenuated vaccine within 30 days before the first dose of EAP
treatment. Note: patients, if enrolled, should not receive live vaccine while
receiving EAP treatments, and up to 30 days after the last dose of EAP treatment.

27. Female patients who are pregnant or breastfeeding, or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 180 days after the last dose of durvalumab+tremelimumab or 90 days after
the last dose of durvalumab monotherapy. Not engaging in sexual activity, as per the
patient's preferred and usual lifestyle, for the total duration of the treatment and
washout periods is an acceptable practice.

28. Previous randomisation or treatment in a previous durvalumab and/or tremelimumab
clinical study regardless of treatment arm assignment.

29. Patients who have received anti-PD-1, anti-PD-L1, or anti-CTLA-4 before the first dose
of EAP treatment.

30. Patient has any condition that, in the opinion of the Treating Physician would
interfere with the evaluation of the programme drug or interpretation of patient
safety

Eligibility Gender
All
Eligibility Age
Minimum: 18 Years ~ Maximum: N/A
Countries
United States
Locations

Research Site
Newark, Delaware, United States

Research Site
Minneapolis, Minnesota, United States

Research Site
Reno, Nevada, United States

Research Site
Morgantown, West Virginia, United States

NCT Number
Keywords
Unresectable Hepatocellular Carcinoma
MeSH Terms
Carcinoma
Carcinoma, Hepatocellular
Durvalumab
Tremelimumab