A Trial of All-trans Retinoic Acid (ATRA) in Advanced Adenoid Cystic Carcinoma

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT03999684
• Collaborator: The V Foundation (Other), ACCRF (Other)
• Enrollment: 18
• Locations: 2
• Arm: 1
• Actual Duration (Months): 8.3
• Patients Per Site: 9
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

This research is studying how safe and effective all-trans retinoic acid (ATRA), is to treat advanced adenoid cystic carcinoma (ACC).

Condition or Disease	Intervention/Treatment	Phase
Adenoid Cystic Carcinoma	Drug: Tretinoin	Phase 2

Detailed Description

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The U.S. Food and Drug Administration (FDA) has not approved all-trans retinoic acid (ATRA) for this specific disease but it has been approved for other uses.

The main purpose of this study is to see how effective all-trans retinoic acid (ATRA) is in treating tumor. Other reasons for conducting the study are:

• To determine for how long all-trans retinoic acid (ATRA) may reduce the size or slow down the growth of tumor

• To evaluate levels of circulating tumor DNA (ctDNA) released in the bloodstream as an indication of the disease activity

• To better understand mechanisms of tumor resistance to ATRA

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of All-trans Retinoic Acid (ATRA) in Advanced Adenoid Cystic Carcinoma
• Actual Study Start Date: Aug 5, 2019
• Actual Primary Completion Date: Apr 15, 2020
• Actual Study Completion Date: Apr 15, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tretinoin -Participants will receive Tretinoin orally divided over two daily doses for days 1 through 14 of a 28-day cycle	Drug: Tretinoin; ATRA control normal cell growth, cell differentiation (the normal process of making cell different from each other), and cell death during embryonic development and in certain tissues later in life. Retinoids effects on the cells are controlled by receptors on the nucleus of each cell (nuclear receptors); Other Names: Tretin-X ATRA

Outcome Measures

Primary Outcome Measures

1. Best Overall Response Rate [up to 8 months]

   CR 0, PR 0, SD 11, PD 5, UE 2 Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. SD=stable disease, PD=progression of disease, UE=unevaluable

Secondary Outcome Measures

1. Complete Response [up to 8 months]

   CR rate captured up to 8 months Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. SD=stable disease, PD=progression of disease, UE=unevaluable

2. Partial Response [up to 8 months]

   PR rate captured up to 8 months Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. SD=stable disease, PD=progression of disease, UE=unevaluable

3. Progression Free Survival [up to 8 months]

   Median PFS or progression free survival Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. SD=stable disease, PD=progression of disease (Progression was defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions), UE=unevaluable

4. Duration Of Therapeutic Response [up to 8 months]

   Duration of CR+PR Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. SD=stable disease, PD=progression of disease, UE=unevaluable

Other Outcome Measures

1. The Inhibitory Effect of Tretinoin on MYB Expression in ACC Tumors [up to 8 months]

   correlative measure of ATRA inhibitory effect measured by IHC (units: % MYB inhibition by IHC quantitative measurement; MYB IHC was performed on stained tissue slides from baseline tumors and scored (%) by an expert pathologist as no/low, medium, and high MYB expressing).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participants must have histologically confirmed adenoid cystic carcinoma with evidence of recurrent, metastatic or advanced, unresectable disease that is not amenable to curative surgery with or without radiotherapy.

• Participants must have at least one RECIST v1.1 measurable non-CNS based lesion, as defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) equal to or greater than 1 cm with CT scans or MR imaging.

• Participants must be willing to undergo fresh tissue core needle biopsy prior to study registration and repeat tumor biopsy while on study for correlatives. Willingness to provide blood samples for research throughout the study is also required.

• Prior systemic therapy: At least 2 weeks must have elapsed since the end of prior chemotherapy, biological agents (4 weeks for anti-cancer monoclonal antibody containing regimens) or any investigational drug product, with adequate recovery of treatment-related toxicity to NCI CTCAE Version 5.0 grade ≤ 1 (or tolerable grade 2) or back to baseline (except for alopecia or neuropathy). Any number of prior therapies for recurrent/metastatic ACC are permitted.

• Be ≥ 18 years of age on day of signing informed consent.

• Have a performance status of 0 or 1 on the ECOG Performance Scale (see Appendix A).

• Participants must have documentation of a new or progressive lesion on a radiologic imaging study performed within 12 months prior to study registration (progression of disease over any interval is allowed) and/or new or worsening disease-related symptoms within 12 months prior to study registration. This assessment is performed by the treating investigator. Evidence of progression by RECIST v1.1 criteria is not required.

• Participants must have normal organ and marrow function as defined below (within 14 days prior to study registration):

• leukocytes ≥ 3,000/mcL

• absolute neutrophil count ≥ 1,500/mcL

• hemoglobin ≥ 9 g/dL without transfusion within 7 days of treatment

• platelets ≥ 100,000/mcL

• total bilirubin ≤ 2x upper limit of normal (ULN)

• AST(SGOT)/ALT(SGPT) ≤ 2.5x institutional ULN or ≤ 5x ULN for those with liver metastases

• serum creatinine ≤ 1.5x ULN OR

• creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels above 1.5x ULN

• coagulation profile INR ≤ 1.5x ULN unless the participant is receiving an anticoagulant

• triglyceride level < 500 mg/dL or < 5.7 mmol/L

• cholesterol level < 400 mg/dL or < 10.34 mmol/L

• Baseline tumor measurements must be documented from imaging within 28 days prior to study registration. Other non-laboratory tests must be performed within 28 days prior to study registration.

• Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 14 days of study registration. Female subjects of childbearing potential should have a negative urine or serum pregnancy test repeated within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

• Female and male subjects of childbearing potential must agree to use an adequate method of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 4 months after completion of tretinoin administration. Contraception is required before starting the first dose of study medication through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. There is a significant risk of fetal malformation if pregnancy occurs while on tretinoin at any dose level, even if for short exposure periods.

• Be willing and able to provide written informed consent for the trial.

Exclusion Criteria:

• Metastatic disease impinging on the spinal cord or threatening spinal cord compression. Patients that have had previous treatment of disease with impinging on the cord with either surgery or radiotherapy with clinical or radiographic evidence of response or stability are eligible.

• Participant has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment), and have no evidence of new or enlarging brain metastases. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability, because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

• Concurrent administration of other cancer specific therapy or investigational agents during the course of this study is not allowed.

• Uncontrolled intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.

• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.

• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

• Subjects who are pregnant, or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. Pregnant women are excluded from this study because tretinoin has the potential for teratogenic or abortifacient effects. Breastfeeding should be discontinued if the mother is treated on this protocol. Women who could potentially become pregnant while undergoing treatment on this protocol must be willing to use 2 methods of contraception.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
2	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• The V Foundation
• ACCRF

Investigators

• Principal Investigator: Glenn J. Hanna, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

• Study Protocol - Dec 31, 2019
• Statistical Analysis Plan - Dec 31, 2019

More Information

Publications

None provided.

• Responsible Party: Glenn J. Hanna, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT03999684
• Other Study ID Numbers: 19-224
• First Posted: Jun 27, 2019
• Last Update Posted: Aug 6, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Glenn J. Hanna, Principal Investigator, Dana-Farber Cancer Institute: Adenoid Cystic Carcinoma
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Adenoid Cystic; Tretinoin

Study Results

Participant Flow

Arm/Group Title	Tretinoin
Arm/Group Description	-Participants will receive Tretinoin orally divided over two daily doses for days 1 through 14 of a 28-day cycle Tretinoin: ATRA control normal cell growth, cell differentiation (the normal process of making cell different from each other), and cell death during embryonic development and in certain tissues later in life. Retinoids effects on the cells are controlled by receptors on the nucleus of each cell (nuclear receptors)
Period Title: Overall Study
STARTED	18
COMPLETED	18
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Tretinoin
Arm/Group Description	-Participants will receive Tretinoin orally divided over two daily doses for days 1 through 14 of a 28-day cycle Tretinoin: ATRA control normal cell growth, cell differentiation (the normal process of making cell different from each other), and cell death during embryonic development and in certain tissues later in life. Retinoids effects on the cells are controlled by receptors on the nucleus of each cell (nuclear receptors)
Overall Participants	18
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	14 77.8%
>=65 years	4 22.2%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	58
Sex: Female, Male (Count of Participants)
Female	11 61.1%
Male	7 38.9%
Race/Ethnicity, Customized (Count of Participants)
White/Caucasian	17 94.4%
Other	1 5.6%
Non-Hispanic	18 100%
Region of Enrollment (participants) [Number]
United States	18 100%

Outcome Measures

1. Primary Outcome

Title	Best Overall Response Rate
Description	CR 0, PR 0, SD 11, PD 5, UE 2 Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. SD=stable disease, PD=progression of disease, UE=unevaluable
Time Frame	up to 8 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tretinoin
Arm/Group Description	-Participants will receive Tretinoin orally divided over two daily doses for days 1 through 14 of a 28-day cycle Tretinoin: ATRA control normal cell growth, cell differentiation (the normal process of making cell different from each other), and cell death during embryonic development and in certain tissues later in life. Retinoids effects on the cells are controlled by receptors on the nucleus of each cell (nuclear receptors)
Measure Participants	18
CR	0 0%
PR	0 0%
SD	11 61.1%
PD	5 27.8%
UE	2 11.1%

2. Secondary Outcome

Title	Complete Response
Description	CR rate captured up to 8 months Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. SD=stable disease, PD=progression of disease, UE=unevaluable
Time Frame	up to 8 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tretinoin
Arm/Group Description	-Participants will receive Tretinoin orally divided over two daily doses for days 1 through 14 of a 28-day cycle Tretinoin: ATRA control normal cell growth, cell differentiation (the normal process of making cell different from each other), and cell death during embryonic development and in certain tissues later in life. Retinoids effects on the cells are controlled by receptors on the nucleus of each cell (nuclear receptors)
Measure Participants	18
Count of Participants [Participants]	0 0%

3. Secondary Outcome

Title	Partial Response
Description	PR rate captured up to 8 months Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. SD=stable disease, PD=progression of disease, UE=unevaluable
Time Frame	up to 8 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tretinoin
Arm/Group Description	-Participants will receive Tretinoin orally divided over two daily doses for days 1 through 14 of a 28-day cycle Tretinoin: ATRA control normal cell growth, cell differentiation (the normal process of making cell different from each other), and cell death during embryonic development and in certain tissues later in life. Retinoids effects on the cells are controlled by receptors on the nucleus of each cell (nuclear receptors)
Measure Participants	18
Count of Participants [Participants]	0 0%

4. Secondary Outcome

Title	Progression Free Survival
Description	Median PFS or progression free survival Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. SD=stable disease, PD=progression of disease (Progression was defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions), UE=unevaluable
Time Frame	up to 8 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tretinoin
Arm/Group Description	-Participants will receive Tretinoin orally divided over two daily doses for days 1 through 14 of a 28-day cycle Tretinoin: ATRA control normal cell growth, cell differentiation (the normal process of making cell different from each other), and cell death during embryonic development and in certain tissues later in life. Retinoids effects on the cells are controlled by receptors on the nucleus of each cell (nuclear receptors)
Measure Participants	18
Median (95% Confidence Interval) [months]	3.2

5. Secondary Outcome

Title	Duration Of Therapeutic Response
Description	Duration of CR+PR Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. SD=stable disease, PD=progression of disease, UE=unevaluable
Time Frame	up to 8 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tretinoin
Arm/Group Description	-Participants will receive Tretinoin orally divided over two daily doses for days 1 through 14 of a 28-day cycle Tretinoin: ATRA control normal cell growth, cell differentiation (the normal process of making cell different from each other), and cell death during embryonic development and in certain tissues later in life. Retinoids effects on the cells are controlled by receptors on the nucleus of each cell (nuclear receptors)
Measure Participants	18
Median (Full Range) [months]	NA

6. Other Pre-specified Outcome

Title	The Inhibitory Effect of Tretinoin on MYB Expression in ACC Tumors
Description	correlative measure of ATRA inhibitory effect measured by IHC (units: % MYB inhibition by IHC quantitative measurement; MYB IHC was performed on stained tissue slides from baseline tumors and scored (%) by an expert pathologist as no/low, medium, and high MYB expressing).
Time Frame	up to 8 months

Outcome Measure Data

Analysis Population Description

only 14 patients had samples evaluable for MYB IHC assessment (of a total of 18)

Arm/Group Title	Tretinoin
Arm/Group Description	-Participants will receive Tretinoin orally divided over two daily doses for days 1 through 14 of a 28-day cycle Tretinoin: ATRA control normal cell growth, cell differentiation (the normal process of making cell different from each other), and cell death during embryonic development and in certain tissues later in life. Retinoids effects on the cells are controlled by receptors on the nucleus of each cell (nuclear receptors)
Measure Participants	14
Low MYB expression	3 16.7%
Medium or high MYB expression	11 61.1%

Adverse Events

Time Frame	8 months
Adverse Event Reporting Description	No difference
Arm/Group Title	Tretinoin
Arm/Group Description	-Participants will receive Tretinoin orally divided over two daily doses for days 1 through 14 of a 28-day cycle Tretinoin: ATRA control normal cell growth, cell differentiation (the normal process of making cell different from each other), and cell death during embryonic development and in certain tissues later in life. Retinoids effects on the cells are controlled by receptors on the nucleus of each cell (nuclear receptors)
All Cause Mortality
	Tretinoin
	Affected / at Risk (%)	# Events
Total	1/18 (5.6%)
Serious Adverse Events
	Tretinoin
	Affected / at Risk (%)	# Events
Total	0/18 (0%)
Other (Not Including Serious) Adverse Events
	Tretinoin
	Affected / at Risk (%)	# Events
Total	14/18 (77.8%)
General disorders
Headache	13/18 (72.2%)
Skin and subcutaneous tissue disorders
Dry Skin	14/18 (77.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.