Study of Axitinib in Patients With Recurred or Metastatic Adenoid Cystic Carcinoma (AxitinibACC)

• ClinicalTrials.gov Identifier: NCT02859012
• Recruitment Status: Completed
• First Posted: August 8, 2016
• Last Update Posted: March 29, 2022
• Sponsor: Seoul National University Hospital
• Information provided by (Responsible Party): Bhumsuk Keam, Seoul National University Hospital

Tracking Information

• First Submitted Date: July 28, 2016
• First Posted Date: August 8, 2016
• Last Update Posted Date: March 29, 2022
• Actual Study Start Date: September 2016
• Actual Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: August 5, 2016): Progression-free survival (PFS) rate [ Time Frame: 6 months ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 5, 2016)

• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 1 year ]
• response rate [ Time Frame: 1 year ]
• overall survival [ Time Frame: 1 year ]
• duration of response [ Time Frame: 1 year ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Axitinib in Patients With Recurred or Metastatic Adenoid Cystic Carcinoma
• Official Title: Randomized Phase II Study of Axitinib in Patients With Recurred or Metastatic Adenoid Cystic Carcinoma
• Brief Summary: To understand efficacy of axitinib in recurred or metastatic adenoid cystic carcinoma

Detailed Description

Adenoid cystic carcinoma (ACC) is a rare variant of adenocarcinoma that occurs in secretory glands such as in salivary glands. Although ACC is histologically low grade and slow-growing, more than half of patients eventually have recurrent and/or metastatic disease.

The natural course of metastatic disease with ACC is relatively indolent; however, most patients with metastatic disease ultimately die from their cancer. The management of recurred / metastatic ACC is a distinct therapeutic challenge because of its insidious local growth pattern, propensity for perineural involvement, tendency for distant metastasis, and pronounced ability to recur over a prolonged period.

2. Current treatment

The role of systemic chemotherapy in ACC is very limited and objective response to any cytotoxic or molecular targeted agent is infrequent, and the optimum regimen is unclear. Because of the rarity of ACC, there are few clinical trials investigating the efficacy of systemic chemotherapy. Recurrent/metastatic ACC is an incurable disease with no standard treatments.

VEGF is highly expressed in ACC and its expression correlates with stage, tumor size, vascular invasion, recurrence and metastasis. High expression of VEGF and Ki-67 were independent poor prognostic factors in ACC. MYB/NFIB translocation has recently identified in ACC and MYB protein over expression was found in ACC. MYB over-expression in ACC has been correlated to the increased expression of genes involved in vascular endothelial growth factor (VEGF), KIT . More than 70% of ACCs highly express the oncogenic transcription factor c-myb, which drives expression of genes that activate VEGFR and c-kit pathways.

Several lines of evidence suggest a function for VEGF, PDGFR signaling in ACC progression. The expressions of NF-kappaB p65, iNOS, and VEGF were related with microvessel density. In vitro, the inhibition of VEGF expression via iNOS gene induced apoptosis of ACC cell lines.

Axitinib (AG-013736; Pfizer) is a multi-targeted small-molecule inhibitor of the receptor tyrosine kinases involved in tumor proliferation and angiogenesis, including VEGFR-1, VEGFR-2 and VEGFR-3, c-kit, platelet-derived growth factor receptor (PDGFR)-α and PFGFR-β. Axitinib (AG-013736) has demonstrated a partial response lasting 4 months in one patient with ACC in a phase I trial . In that aspect, Ho et al. conducted phase II study with axitinib in ACC. Interestingly, response rate was 9.1% and tumor shrinkage was observed in 66.7%

Besides of axitinib, other antiangiogenic agents such as sutene or dovitinib showed promising activity in ACC. Dovitinib, which is pan FGFR , VEGF, PDGFR inhibitor showed one confirmed partial response PR (3.1%) and three unconfirmed PR (9.3%). Interestingly, hyperphosphatemia was not observed in this study, and one PR patients showed strong PDGFR beta positivity, which suggests that antiangiogenic pathway is more important than FGFR pathway.

3. Gap, issue or problem that needs to be addressed

Based on these evidences which suggest a function for VGFR, PDGFR signaling in ACC tumorigenesis and progression, the use of axitinib is reasonable and valuable.

However, the huge gap in ACC trial is lack of randomization trial. Until now, there is no randomized trial in ACC because of its rarity. Hence there is no confirmatory trial in ACC. Without randomization trial, we can not say the real efficacy of axitinib.

So we design multicenter randomized trial of axtinib in ACC to confirm the efficacy of axitinib in this orphan disease.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Recurrent ACC, metastaticACC, Unreaectable ACC

Intervention

• Drug: Axitinib
  Dosing schedule: 5mg twice per day orally (4 weeks is considered as 1 cycle)
  Other Name: Inlyta
• Other: Observation
  this group is observational ones.

Study Arms

• Experimental: axitinib
  Axitinib 5 mg twice (10mg) daily po medication until progression or development of unacceptable toxicity (4 weeks is considered as one cycle).
  Intervention: Drug: Axitinib
• Active Comparator: observation
  Observation. if disease progression is detected, cross-over will be permitted.
  Intervention: Other: Observation

• Publications *: Kang EJ, Ahn MJ, Ock CY, Lee KW, Kwon JH, Yang Y, Choi YH, Kim MK, Ji JH, Yun T, Nam BH, Kim SB, Keam B. Randomized Phase II Study of Axitinib versus Observation in Patients with Recurred or Metastatic Adenoid Cystic Carcinoma. Clin Cancer Res. 2021 Oct 1;27(19):5272-5279. doi: 10.1158/1078-0432.CCR-21-1061.

Recruitment Information

• Recruitment Status: Completed
• Estimated Enrollment (submitted: August 5, 2016): 60
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: August 2020
• Actual Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Histologically confirmed adenoid cystic carcinoma
2. Local, locally-advanced or metastatic disease documented as having shown progression on a scan (CT, MRI, MIBI scan) or X-ray taken >9 months prior to baseline compared to a previous image. Progression must be documented according to RECIST 1.1 criteria.
3. Disease that is not amenable to surgery, radiation or combined modality therapy with curative intent
4. Presence of at least one measurable target lesion for further evaluation according to RECIST 1.1 criteria
5. 18 years or older
6. ECOG performance status 0, 1

7. Adequate organ function

   • ANC ≥ 1500/ μL
   • Platelets ≥100,000/ μL
   • Hemoglobin ≥ 9.0 g/dL
   • Serum creatinine ≤1.5 x ULN
   • Serum bilirubin ≤1.5 x ULN
   • AST, ALT, ≤3.0 x ULN (regardless of liver metastasis)
8. A patient with the willingness to comply with the study protocol during the study period and capable of complying with it
9. A patient who signed the informed consent prior to the participation of the study and who understands that he/she has a right to withdrawal from participation in the study at any time without any disadvantages.

Exclusion Criteria:

1. A patient with no measurable disease
2. Prior chemotherapy, radiation therapy or surgery within 4 weeks prior to study entry except palliative radiotherapy to non-target lesions (within 2 weeks prior to study entry)
3. A patient with intestinal obstruction or impending obstruction, recent active upper GI bleeding
4. A pregnant or lactating patient
5. A patient of childbearing potential without being tested for pregnancy at baseline or with being tested for positive. (A postmenopausal woman with the amenorrhea period of at least 12 months or longer is considered to have non-childbearing potential)
6. A man or woman of childbearing potential who has no willingness to use a contraceptive measure during the study
7. A patient with history of another malignant disease within past 5 years, except curatively treated basal cell carcinoma of skin, early gastric cancer and cervical carcinoma in situ.
8. A patient with history of uncontrolled seizures, central nervous system disorder or psychiatric disorders that are considered clinically significant by the investigator that would prohibit the understanding of informed consent or that may be considered to interfere with the compliance of the administration of the study medications.
9. A patient with clinically significant heart disease (e.g. congestive heart failure, symptomatic coronary artery diseases, cardiac arrhythmia, etc) or myocardial infarction within past 12 months.
10. A patient with organ transplantation requiring immunosuppressive therapy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Korea, Republic of

Administrative Information

• NCT Number: NCT02859012
• Other Study ID Numbers: Axitinib in ACC
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bhumsuk Keam, Seoul National University Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Seoul National University Hospital
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Bhumsuk Kim, Ph.D.; Seoul National University Hospital

• PRS Account: Seoul National University Hospital
• Verification Date: March 2022