A Phase II, single arm Study of avelumab in combination with Axitinib in Patients with unresectable/metastatic Gastrointestinal Stromal Tumor after failure of standard therapy - AXAGIST

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

8 May 2019 → 31 Dec 2025

Decision date (initial)

2025-01-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-519176-95-00

EudraCT number

2018-003998-96

ClinicalTrials.gov

NCT04258956

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess anti-tumor activity of avelumab in combination with axitinib in patients with unresectable/metastatic GIST after progression on second or third line treatment (after failure on at least of imatinib and sunitinib) in terms of progression-free survival (PFS)

Secondary objectives 4

1. To evaluate the objective response rate (ORR), duration of response (DoR), disease control (DC) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)
2. To evaluate overall survival time (OS)
3. To evaluate safety and tolerability of avelumab + axitinib
4. To explore potential biomarkers associated with clinical efficacy (ORR, DC, PFS and OS) by analyzing biomarker measures within the tumor microenvironment and peripheral blood in comparison to clinical outcomes

Conditions and MedDRA coding

Gastrointestinal Stromal Tumors (GIST)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Signed written informed consent.
2. Male or female subjects aged ≥ 18 years.
3. Histologically proven locally advanced or metastatic GIST. C-Kit (CD117) positive tumors detected by immunohistochemistry
4. Known mutational status KIT or PDGFRA.
5. Documented disease progression (as per RECIST 1.1) within 3 months before study entry
6. No more than 3 previous lines of treatment, which must include imatinib and sunitinib
7. Performance status ≤ 2 at trial entry and an estimated life expectancy of at least 3 months.
8. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1. Clinically and/or radiographically documented measurable disease within 21 days prior to registration 1) CT-scan, physical exam ≥10 mm 2) Chest X-ray ≥20 mm 3) Lymph node short axis ≥15 mm. All radiology studies must be performed within 21 days prior to registration.
9. Adequate hematological function defined by the following laboratory tests results, obtained within 14 days prior to initiation of study treatment - white blood cell (WBC) count ≥ 3 × 109/L with absolute neutrophil count (ANC) ≥ 1.5 × 109/L, - lymphocyte count ≥ 0.5 × 109/L, - platelet count ≥ 100 × 109/L, - hemoglobin ≥ 9 g/dL (patients may be transfused).
10. Adequate hepatic function defined by - total bilirubin level ≤ 1.5 × the upper limit of normal range (ULN), - an AST level ≤ 2.5 × ULN, and an ALT level ≤ 2.5 × ULN or, for subjects with documented metastatic disease to the liver, AST and ALT levels ≤ 5 × ULN.
11. Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 ml/min on the basis of the Cockroft- Gault glomerular filtration rate estimation: (140-age) x (weight in kg) x (0,85 if female)/72x(serum creatinine in mg/dl)
12. No clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), Uncontrolled hypertension (systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg , unstable angina, congestive heart failure (≥2 New York Heart Association Classification medication) serious cardiac arrhythmia. All other significant diseases (e.g., inflammatory bowel disease), which, in the opinion of the investigator, might impair the subject’s tolerance of trial treatment;
13. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
14. Patients not receiving anticoagulant medication who have an International Normalized Ratio (INR) >1.5 or an activated partial thromboplastin time (aPTT) >1.5 x ULN within 7 days prior to first study treatment. Note: Patients receiving full dose oral or parenteral anticoagulants may be included in the study as long as anticoagulant dosing has been stable for at least 2 weeks prior to study entry and the appropriate coagulation monitoring tests are within local therapeutic limits;
15. Effective contraception for both male and female subjects if the risk of conception exists. (Note: The effects of the study drugs on the developing human fetus are unknown. Thus, women of childbearing potential and men must agree to use effective contraception, defined as 2 barrier methods e.g. implants, injectables, combined oral contraceptives in combination with a barrier method, some intrauterine contraceptive devices, sexual abstinence, or a vasectomized partner;)
16. Availability of representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks.

Exclusion criteria 21

1. Concurrent anticancer treatment within 14 days before the start of trial treatment (e.g., cytoreductive therapy, radiotherapy [with the exception of palliative bone directed radiotherapy], immune therapy, or cytokine therapy except for erythropoietin); major surgery within 28 days before the start of trial treatment (excluding prior diagnostic biopsy); use of hormonal agents within 7 days before the start of trial treatment; or use of any investigational drug within 28 days before the start of trial treatment.
2. Patients with PDGFRA D842V mutations are not eligible for this study.
3. Previous treatment with anti-PD-1 or anti-PD-L1 antibodies, previous therapy with axitinib.
4. Persisting toxicity related to prior therapy Grade > 1 CTCAE v 4.0,
5. Major surgical procedure within 28 days prior to the first study treatment, or anticipation of the need for major surgery during the course of the study treatment; or minor surgical procedures, within 24 hours prior to the first study treatment;
6. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
7. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration except for adrenal replacement steroid. The use of inhaled corticosteroids for chronic obstructive pulmonary disease is allowed.
8. History of abdominal fistula, grade 4 bowel obstruction or gastrointestinal perforation, intra-abdominal abscess within 6 months of enrollment;
9. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan
10. Significant acute or chronic infections including, among others: positive testing for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
11. Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test at screening. Patients with past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at screening, are eligible for the study.
12. Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test and positive HCV RNA test at screening
13. Active tuberculosis
14. Severe infection within 2 weeks prior initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteriemia or severe pneumonia
15. Brain or leptomeningeal metastases, history of intracranial hemorrhage
16. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study
17. Known alcohol or drug abuse
18. Inability or unwillingness to swallow pills
19. Pregnant or breastfeeding, or intending to become pregnant during the study. Woman of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.
20. Symptomatic brain metastases, history of intracranial hemorrhage
21. Previous enrollment in this study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Rate of Participants Achieving 3-Month Progression-Free Survival (PFSR) [Rate of participants who are progression-free at 3 months after the start of protocol therapy, using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 criteria. Progression-free survival (PFS) is defined as the time from treatment initiation until documented disease progression or death (by any cause, in the absence of progression)].

Secondary endpoints 9

1. Progression free survival (PFS) [time from treatment initiation to date of first documentation of progression of disease assessed by the Investigator (by RECIST version 1.1) or death due to any cause]
2. Overall survival (OS) [time from the date of treatment initiation until the date of death from any cause]
3. 1-year overall survival (OS) rate [proportion of patients that survive more than 1 year]
4. Overall response rate (ORR) [ORR is defined as the proportion of patients with objective response [confirmed complete (CR) or partial response (PR) according to RECIST Version 1.1]
5. Duration of response (DoR) [the time from documentation of tumor response to disease progression]
6. Disease control rate (DCR) [patients whose best response was CR or PR or Stable Disease (SD)]
7. Adverse events (graded according to the Common Toxicity Criteria for the Adverse Events, CTC-AE, version 4.0) assessed every 4 weeks
8. Relationship between PDL-1 expression and measures of efficacy, including ORR, DCR, PFS and OS
9. Relationship between biomarkers in blood/tissue and efficacy, including ORR, DCR, PFS and OS

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy

Sponsor organisation

Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy

Address

Ul. Wilhelma Konrada Roentgena 5

City

Warsaw

Postcode

02-781

Country

Poland

Scientific contact point

Organisation

Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy

Contact name

główny badacz

Public contact point

Organisation

Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy

Contact name

Dział Badań Klinicznych NIO-PIB

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications