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JOURNAL ONKOLOGIE – STUDIE

RP3 in Combination With 1L or 2L Therapy in Patients With Locally Advanced Unresectable or Metastatic HCC

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NCT-Nummer:
NCT05733598

Studienbeginn:
April 2024

Letztes Update:
22.12.2023

Wirkstoff:
RP3, Atezolizumab, Bevacizumab

Indikation (Clinical Trials):
Carcinoma, Carcinoma, Hepatocellular

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
Replimune Inc.

Collaborator:
Roche Pharma AG

Studienleiter

Jaroslaw Jac, MD
Study Chair
Replimune Inc.

Kontakt

Studienlocations
(3 von 26)

Uniklinikum Heidelberg National Center for Tumors Heidelberg (NCT)
69120 Heidelberg
(Baden-Württemberg)
Germany» Google-Maps
University Hospital Leipzig Clinic and Polyclinic for Oncology, Gastroenterology, Hepatology, Pneumatology, Infectiology
04103 Leipzig
(Sachsen)
Germany» Google-Maps
Ansprechpartner:
Florian van Bömmels» Ansprechpartner anzeigen
Royal Free London NHS Foundation Trust
NW3 2QG London
United Kingdom» Google-Maps
Alle anzeigen

Studien-Informationen

Detailed Description:

RP3 is a genetically modified herpes simplex type 1 virus (HSV-1) that expresses exogenous

genes (anti-CTLA-4 antibody, CD40 ligand and h4-1BBL) designed to directly kill tumor cells

and generate a systemic anti-tumor immune response

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Male or female ≥18 years of age.

2. Has locoregionally advanced unresectable, recurrent, and/or metastatic HCC, with the

diagnosis confirmed by histologic or cytologic analysis or clinical features plus

imaging criteria (using LI-RADS v2018) according to the American Association for the

Study of Liver Diseases criteria for patients with cirrhosis.

3. Child-Pugh A, as determined within 14 days before first study treatment.

4. Has at least 1 measurable tumor of ≥1cm in longest diameter (or ≥1.5cm shortest

diameter for lymph nodes)as defined by RECIST 1.1.

5. Has injectable tumor(s), which alone or in aggregate, total at least 1cm in diameter.

6. Must be willing to consent to provide fresh tumor biopsy sample or archival tumor

biopsy sample obtained within 60 days before initiation of study treatment.

7. Has adequate hematologic function, including:

- White blood cell (WBC) count ≥2.0 × 109/L

- Absolute neutrophil count (ANC) ≥1.5 × 109/L(without granulocyte-colony

stimulating factor support)

- Platelet count ≥50× 109/L(without transfusion)

- Hemoglobin ≥8.5 g/dL (may have received transfusions; however, patient must not

be transfusion-dependent).

8. Has adequate hepatic function including:

- Total bilirubin ≤3.0× upper limit of normal (ULN)

- Aspartate aminotransferase (AST) alanine aminotransferase (ALT), and alkaline

phosphatase (ALP) ≤5.0 × ULN.

9. Has adequate renal function, defined as serum creatinine ≤1.5 × ULN or creatinine

clearance ≥30 mL/minute(measured using Cockcroft-Gault formula).

10. Serum albumin ≥2.8 g/dL.

11. Prothrombin time (PT) ≤1.5 × ULN (or international normalization ratio [INR] ≤1.7) and

partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤1.5

× ULN.

Note: Patients who are on a stable dose of long-term coumadin therapy may be enrolled

if the target INR is≤2.5, provided that the INR can be safely reversed to≤1.7

temporarily around the time of RP3 injection.

12. Eastern Cooperative Oncology Group (ECOG)performance status 0 or 1.

13. Female and male patients of reproductive potential must agree to avoid becoming

pregnant or impregnating a partner and adhere to highly effective contraception

requirements during the treatment period and for at least (a) 90 days after the last

dose of RP3 or (b) 5 months after the last dose of atezolizumab or (c) 6 months after

the last dose of bevacizumab, whichever is longer.

14. Women of childbearing potential must have a negative serum beta-human chorionic

gonadotropin (β-hCG) test with a minimum sensitivity of 25 IU/L or equivalent units of

β-hCG within 72 hours before the first dose and a negative urine pregnancy test on

Dose1 Day1.

15. Capable of giving signed informed consent which includes willingness to comply with

the requirements and restrictions listed in the informed consent form and in this

protocol.

1L Cohort only:

16. Patient is eligible for 1L systemic therapy with atezolizumab and bevacizumab Note:

Patients who have received prior local therapy (eg, radiofrequency ablation, percutaneous

ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound,

transarterial chemoembolization, transarterial embolization) are eligible provided the

target lesion(s) have not been previously treated with local therapy or have subsequently

progressed in accordance with RECIST 1.1.

2L Cohort only:

17. Must have progressed on or after 1 systemic therapy, which must have included anti-PD-1

or anti-PD-L1therapy (eg, atezolizumab plus bevacizumab combination, durvalumab plus

tremelimumab combination, durvalumab, pembrolizumab, or nivolumab monotherapy or nivolumab

plus ipilimumab or lenvatinib plus pembrolizumab combination) as their immediate prior

treatment regimen.

Exclusion Criteria:

1. Child-Pugh B or C.

2. Patients with untreated or incompletely treated esophageal and/or gastric varices with

active/recent bleeding or at high-risk for bleeding.

Note: All patients must undergo an esophagogastroduodenoscopy, and all varices

(irrespective of size) must be assessed and treated per local standards of care before

enrollment. Patients who have undergone endoscopic management of all known varices

with 120 days before initiation of study treatment do not need to repeat the

procedure.

3. Significant bleeding event within the last 12 months that places the patient at

unjustifiable risk for bleeding from intratumoral injection procedures, based on

Investigator or interventional radiologist assessment.

4. Macroscopic intravascular invasion into the hepatic and/or segmental portal vein(s),

main or segmental hepatic veins and/or ateries, inferior vena cava, and/or other major

blood vessel, or into the hepatic and/or common bile duct(s)

5. Histologic evidence of fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma

with HCC, or other rare histologic HCC variants.

6. History of medically refractory hepatic encephalopathy and/or hepato-renal syndrome.

7. Disease that is amenable to surgical and/or standard locoregionally directed

therapies.

8. Presence of liver tumors that are estimated to invade more than one-third of the

liver.

9. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring drainage

within 7days before enrollment.

10. Known acute or chronic hepatitis B (defined as hepatitis B surface antigen [HBsAg]

reactive) or known acute or chronic hepatitis C virus (defined as HCV RNA

[qualitative] is detected).

Note: Patients who have been effectively treated are eligible for enrollment. Patients

must be negative for HBsAg and HCV RNA

11. Known human immunodeficiency virus (HIV) infection.

Note: Testing for HIV is not required unless mandated by local health authority or

clinically indicated.

12. Active significant herpetic infections or prior complications of HSV-1 infection (eg,

herpetic keratitis or encephalitis) or requires intermittent or chronic use of

systemic (oral or IV) antivirals with known antiherpetic activity (eg, acyclovir).

Note: Patients with sporadic cold sores may be enrolled if no active cold sores are

present at the time of Dose1 Day 1.

13. Systemic infection requiring IV antibiotics or other serious infection within 14days

before initiating study therapy.

14. Received a live vaccine within 28 days before the first dose of study treatment.

15. Central nervous system (CNS) metastases and/or carcinomatous meningitis.

16. Prior malignancy, other than HCC, active within the previous 3 years, except for

localized cancers that have apparently been cured including basal or squamous cell

skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix,

or breast.

17. Is currently participating in or has participated in a study of an investigational

agent or has used an investigational device within 4 weeks before the first dose of

study treatment. Note: Patients who have entered the follow-up phase of an

investigational study may participate if it has been more than 4 weeks after the last

dose of the previous investigational agent.

18. Systemic anticancer therapies within 4 weeks of the first dose of study drug. The

prior anti-PD-1 or anti-PD-L1 containing regimen is excluded from this requirement for

the 2Lcohort.

Note: Patients must have recovered (to Grade ≤1 or baseline) from all AEs due to

previous therapies. Patients with Grade ≤2 neuropathy may be eligible if approved by

the Medical Monitor.

19. Received radiotherapy within 2 weeks of start of study treatment. Patients must have

recovered from all radiation-related toxicities (except for radiation-induced

xerostomia), not require corticosteroids, and not have had radiation pneumonitis. A

1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to

non-CNS disease.

20. Received prior treatment with an oncolytic virus therapy.

21. History of significant cardiac disease including myocarditis or congestive heart

failure (defined as New York Heart Association Functional Classification III or IV),

or unstable angina, serious uncontrolled cardiac arrhythmia, or myocardial infarction

within 6 months of enrollment.

22. Uncontrolled infection.

23. History of interstitial lung disease, idiopathic pulmonary fibrosis, organizing

pneumonia (eg, bronchiolitis obliterans), non-infectious pneumonitis that required

steroids, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active

pneumonitis on screening chest CT scan.

Note: History of radiation pneumonitis in a prior radiation field (radiation fibrosis)

is permitted.

24. Active tuberculosis.

25. History or evidence of psychiatric, substance abuse, or any other clinically

significant disorder, condition, or disease (except for those outlined above) that, in

the opinion of the Investigator or the Medical Monitor, would pose a risk to patient

safety or interfere with the study evaluation, procedures, or completion.

26. History or current evidence of any condition, therapy, or laboratory abnormality that

might confound the results of the study, interfere with the patient's participation

for the full duration of the study, or is not in the best interest of the patient to

participate, in the opinion of the Investigator.

27. Active, known, or suspected autoimmune disease requiring systemic treatment. Note:

Patients with type 1 diabetes mellitus and/or hypothyroidism requiring only hormone

replacement, and/or with autoimmune skin disorders (such as vitiligo, psoriasis, or

alopecia) not requiring systemic treatment, and/or prior non-serious autoimmune

conditions not expected to recur are permitted to enroll.

28. Conditions requiring treatment with immunosuppressive doses (>10 mg per day of

prednisone or equivalent) of systemic corticosteroids within 14 days before Dose1 Day

1. Note: Patients who require a brief course (≤7 days) of corticosteroids (eg, as

prophylaxis for imaging studies due to hypersensitivity to contrast agents) are not

excluded. Physiologic replacement doses of systemic corticosteroids are permitted,

only if the dose does not exceed 10 mg/day prednisone equivalent.

29. History of allergy or sensitivity to study drug components or prior monoclonal

antibody treatment; known hypersensitivity to Chinese hamster ovary cell products or

to any component of the atezolizumab or bevacizumab formulation.

30. History of allergy or sensitivity to study drug components or prior monoclonal

antibody treatment; known hypersensitivity to Chinese hamster ovary cell products or

to any component of the atezolizumab or bevacizumab formulation. \History of

life-threatening toxicity related to prior immune therapy (eg, anti-cytotoxic T

lymphocyte antigen 4 or anti-PD-1/anti-PD-L1 treatment or any other antibody or drug

specifically targeting T-cell co-stimulation or immune checkpoint pathways [eg, CD40,

4-1BB]) except those that are unlikely to recur or are expected to be manageable with

standard countermeasures (eg, hormone replacement after adrenal crisis). Individual

cases should be discussed with Medical Monitor as appropriate.

31. Conditions in which anticoagulant therapies cannot be safely stopped in the

periprocedural period or patients on coumadin with a target INR >2.5 or that cannot be

temporarily reversed toINR≤1.7 around the time of intratumoral injections.

32. Treatment with botanical preparations (eg, herbal supplements or traditional Chinese

medicines) intended for general health support or to treat the disease under study

within 2weeks before initiating study treatment.

33. Prior organ transplantation including allogeneic stem-cell transplantation.

34. Major surgery within 28days before starting bevacizumab or anticipated major surgery

while on study.

Note: If a patient received major surgery, they must have recovered adequately from the

intervention before starting study treatment and must have adequate wound healing, based on

surgeon's assessment, before starting bevacizumab.

Studien-Rationale

Primary outcome:

1. Overall Response Rate per modified RECIST 1.1 (Time Frame - From Day 1 to documented progression of disease (up to 3 years)):
Percentage of subjects achieving objective response (complete response + partial response)



Secondary outcome:

1. Frequency, Nature, and Severity of TEAEs and SAEs (Time Frame - From Screening through 60 days after last dose of RP3, or 135 days after last dose of atezolizumab/bevacizumab):
Percentage of subjects with TEAEs and SAEs

2. Overall Response Rate per RECIST modified for use in the HCC setting (Time Frame - From Day 1 to documented progression of disease (up to 3 years)):
Percentage of subjects with objective response (complete response + partial response) per RECIST modified for use in the HCC setting

3. Duration of Response (Time Frame - From Day 1 to documented progression of disease (up to 3 years)):
Duration of response is defined as the time from documented response until the date of progression of disease, which was subsequently confirmed or with no further follow-up, or death due to any cause, whichever occurs first

4. Duration of Clinical Benefit (Time Frame - From Day 1 to documented progression of disease (up to 3 years)):
Duration of clinical benefit is defined as the time from the first day of study treatment to last progression of disease, which was subsequently confirmed or with no further follow-up for response, or death due to any cause, whichever occurs first, for subjects who achieve complete response, partial response, or stable disease

5. Complete response rate (Time Frame - From Day 1 to documented progression of disease (up to 3 years)):
Percentage of subjects achieving complete response

6. Clinical Benefit Rate (Time Frame - From Day 1 to documented progression of disease (up to 3 years)):
Percentage of subjects achieving complete response, partial response, or stable disease

7. Progression-free Survival (Time Frame - From Day 1 to documented progression of disease (up to 3 years)):
Progression-free survival is defined as the time from the first day of study treatment to the date of progression of disease, which was subsequently confirmed, or death by any cause, whichever occurs first

8. Overall Survival (Time Frame - From Day 1 to date of death by any cause (up to 3 years)):
Overall survival is defined as the time from the first day of study treatment to the date of death by any cause

Studien-Arme

  • Experimental: 1L:RP3 w/atezolizumab + bevacizumab in advanced HCC not amenable to resection/locoregional therapies
    RP3 will be injected by direct or image-guided injection into injectable tumors (eg,primary sitehepatic tumors, hepatic metastases, non-hepatic metastases, visceral, or nodal tumors).
  • Experimental: 2L:RP3 w/atezolizumab + bevacizumab in advanced HCC not amenable to locoregional thrpy after PD(L)1
    RP3 will be injected by direct or image-guided injection into injectable tumors (eg,primary sitehepatic tumors, hepatic metastases, non-hepatic metastases, visceral, or nodal tumors).

Geprüfte Regime

  • RP3:
    Genetically modified herpes simplex type 1 virus
  • atezolizumab:
    anti-PD-L1 monoclonal antibody
  • bevacizumab:
    anti-VEGF therapy

Quelle: ClinicalTrials.gov


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