Dose-finding Study of APD403 to Prevent Nausea and Vomiting After Chemotherapy

• Sponsor: Acacia Pharma Ltd (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01857232
• Collaborator: (none)
• Enrollment: 342
• Location: 1
• Arms: 5
• Duration (Months): 16
• Patients Per Site Per Month: 21.3

Study Details

Study Description

Brief Summary

Comparison of efficacy of APD403 at preventing delayed sickness in patients who have received cancer chemotherapy

Condition or Disease	Intervention/Treatment	Phase
CINV	Drug: Ondansetron; Drug: Placebo; Drug: Dexamethasone; Drug: Fosaprepitant; Drug: APD403 IV; Drug: APD403 oral	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 342 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Randomised, Double-blind, Dose-finding Phase II Study to Assess the Efficacy of APD403 in the Prevention of Nausea and Vomiting Caused by Cisplatin- or Anthracycline/Cyclophosphamide (AC)-Based Chemotherapy
• Study Start Date: Oct 1, 2013
• Actual Primary Completion Date: Feb 1, 2015
• Actual Study Completion Date: Feb 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Other: Control OND + DEX + FOS followed by oral DEX	Drug: Ondansetron; 5HT3-antagonist; Drug: Dexamethasone; Corticosteroid; Drug: Fosaprepitant; NK1 antagonist
Placebo Comparator: Placebo OND + APD403 followed by oral PLACEBO	Drug: Ondansetron; 5HT3-antagonist; Drug: Placebo; Comparator; Drug: APD403 IV; Amisulpride IV 20 mg
Experimental: Low dose APD403 OND + APD403 followed by oral APD403 low dose	Drug: Ondansetron; 5HT3-antagonist; Drug: APD403 IV; Amisulpride IV 20 mg; Drug: APD403 oral; Amisulpride oral 10, 20 or 40 mg
Experimental: Mid dose APD403 OND + APD403 followed by oral APD403 mid dose	Drug: Ondansetron; 5HT3-antagonist; Drug: APD403 IV; Amisulpride IV 20 mg; Drug: APD403 oral; Amisulpride oral 10, 20 or 40 mg
Experimental: High dose APD403 OND + APD403 followed by oral APD403 high dose	Drug: Ondansetron; 5HT3-antagonist; Drug: APD403 IV; Amisulpride IV 20 mg; Drug: APD403 oral; Amisulpride oral 10, 20 or 40 mg

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Delayed Phase Complete Response(CR) [24-120 hours]

   Delayed phase complete response (CR), defined as an absence of emetic episodes and no rescue medication use in the period from 24 to 120 hours after the initiation of chemotherapy. The primary endpoint was analysed separately in the strata of chemotherapy regimen and gender, and in the strata of country.

Secondary Outcome Measures

1. Number of Participants With CR in the Overall Phase. [0 to 120 hours after the initiation of chemotherapy]

   CR defined as no emesis and no use of rescue medication, in the overall phase (0 to 120 hours after the initiation of chemotherapy)

Eligibility Criteria

Criteria

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

Inclusion criteria

• Male or female patients ≥ 18 years of age

• Ability and willingness to give written informed consent

• Patients scheduled to receive, on day 1 of their chemotherapy, either: (i) a first cisplatin chemotherapy infusion at a dose of ≥70 mg/m2 (males and females); or (ii) a first infusion of cyclophosphamide at a dose of 500-1500 mg/m2 in combination with either epirubicin at a dose of 60-100 mg/m2 or doxorubicin at a dose of 40-60 mg/m2 (females only)

• Karnofsky performance score ≥ 60%

• Adequate cardiac, hepatic and renal function

• QTc interval < 500 ms

• Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < 5 x upper limit normal (ULN)

• Bilirubin < 5 x ULN

• Creatinine < 3 x ULN

• Adequate haematological function

• Haemoglobin ≥ 8 g/dL

• White blood count ≥ 3.0 x 109/L

• Platelet count ≥ 100 x 109/L

• For females of child-bearing potential: ability and willingness to use a highly effective form of contraception (e.g., abstinence from sexual intercourse, surgical sterilisation (of subject or partner) or a double-barrier method of contraception such as either an intra-uterine device (IUD) or an occlusive cap with spermicide, in conjunction with partner's use of a condom) during the study and for a period of at least 48 hours afterwards

Exclusion Criteria

• Patients scheduled to receive, prior to or in the 120 hours after cisplatin or AC, any other chemotherapeutic agent with a high or moderate emetic risk

• Patients who have previously received anti-neoplastic chemotherapy

• Patients scheduled to receive paclitaxel or docetaxel during the first cycle of their chemotherapy

• Patients undergoing abdominal or pelvic irradiation within 48 hours prior to screening or scheduled to receive abdominal or pelvic irradiation between screening and 24 hours after cisplatin or AC administration

• Patients with a known prolactin-dependent tumour (e.g. pituitary gland prolactinoma or confirmed prolactin-dependent breast cancer) or phaeochromocytoma

• Patients with a pre-existing vestibular disorder

• Patients being treated with regular anti-emetic therapy including corticosteroids

• Patients receiving inhaled corticosteroids, unless started more than one month prior to the expected date of study entry

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Odense University Hospital	Odense		Denmark

Sponsors and Collaborators

• Acacia Pharma Ltd

Investigators

• Principal Investigator: Jørn Herrstedt, MD, Odense University Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Acacia Pharma Ltd
• ClinicalTrials.gov Identifier: NCT01857232
• Other Study ID Numbers: DN10016
• First Posted: May 20, 2013
• Last Update Posted: Nov 25, 2020
• Last Verified: Nov 1, 2020

• Additional relevant MeSH terms: Vomiting; Dexamethasone; Ondansetron; Fosaprepitant; Aprepitant

Study Results

Participant Flow

Arm/Group Title	Control	Placebo	APD403 10MG	APD403 20MG	ADP403 40MG
Arm/Group Description	ACUTE (day 1): IV OND + FOS + DEX • DELAYED (days 2 to 4): Oral DEX	ACUTE (day 1): IV OND + APD403 20 mg DELAYED (days 2 to 4): Oral Placebo	ACUTE (day 1): IV OND + APD403 20 mg • DELAYED (days 2 to 4): Oral APD403 10 mg	ACUTE (day 1): IV OND + APD403 20 mg • DELAYED (days 2 to 4): Oral APD403 20 mg	ACUTE (day 1): IV OND + APD403 20 mg • DELAYED (days 2 to 4): Oral APD403 40 mg
Period Title: Overall Study
STARTED	69	67	67	70	69
Evaluable ITT	66	66	63	68	65
COMPLETED	61	65	63	68	63
NOT COMPLETED	8	2	4	2	6

Baseline Characteristics

Arm/Group Title	Control ( Dexamethazon)	Placebo	APD403 10MG	APD403 20MG	ADP403 40MG	Total
Arm/Group Description	ACUTE (day 1): IV OND + FOS + DEX • DELAYED (days 2 to 4): Oral DEX	ACUTE (day 1): IV OND + APD403 20 mg DELAYED (days 2 to 4): Oral Placebo	ACUTE (day 1): IV OND + APD403 20 mg • DELAYED (days 2 to 4): Oral APD403 10 mg	ACUTE (day 1): IV OND + APD403 20 mg • DELAYED (days 2 to 4): Oral APD403 20 mg	ACUTE (day 1): IV OND + APD403 20 mg • DELAYED (days 2 to 4): Oral APD403 40 mg	Total of all reporting groups
Overall Participants	66	66	63	68	65	328
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	58.1 (10.38)	57.3 (11.01)	56.9 (11.24)	56.6 (10.53)	56.5 (10.59)	57.1 (10.70)
Sex: Female, Male (Count of Participants)
Female	51 77.3%	51 77.3%	52 82.5%	52 76.5%	51 78.5%	257 78.4%
Male	15 22.7%	15 22.7%	11 17.5%	16 23.5%	14 21.5%	71 21.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
White	65 98.5%	64 97%	62 98.4%	68 100%	64 98.5%	323 98.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 1.5%	2 3%	1 1.6%	0 0%	1 1.5%	5 1.5%
Region of Enrollment (Number) [Number]
Denmark	16 24.2%	12 18.2%	13 20.6%	17 25%	15 23.1%	73 22.3%
Germany	23 34.8%	23 34.8%	19 30.2%	21 30.9%	22 33.8%	108 32.9%
United Kingdom	27 40.9%	31 47%	31 49.2%	30 44.1%	28 43.1%	147 44.8%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Delayed Phase Complete Response(CR)
Description	Delayed phase complete response (CR), defined as an absence of emetic episodes and no rescue medication use in the period from 24 to 120 hours after the initiation of chemotherapy. The primary endpoint was analysed separately in the strata of chemotherapy regimen and gender, and in the strata of country.
Time Frame	24-120 hours

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Control	PLACEBO	APD403 10MG	ADP421 20MG	APD421 40MG
Arm/Group Description	ACUTE (day 1): IV OND + FOS + DEX • DELAYED (days 2 to 4): Oral DEX	ACUTE (day 1): IV OND + APD403 20 mg • DELAYED (days 2 to 4): Oral Placebo	ACUTE (day 1): IV OND + APD403 20 mg • DELAYED (days 2 to 4): Oral APD403 10 mg	ACUTE (day 1): IV OND + APD403 20 mg • DELAYED (days 2 to 4): Oral APD403 20 mg	ACUTE (day 1): IV OND + APD403 20 mg • DELAYED (days 2 to 4): Oral APD403 40 mg
Measure Participants	66	66	63	68	65
Count of Participants [Participants]	37 56.1%	13 19.7%	27 42.9%	21 30.9%	20 30.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, APD403 10MG
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, ADP421 20MG
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0987
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, APD421 40MG
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1041
	Comments
	Method	Regression, Logistic
	Comments

2. Secondary Outcome

Title	Number of Participants With CR in the Overall Phase.
Description	CR defined as no emesis and no use of rescue medication, in the overall phase (0 to 120 hours after the initiation of chemotherapy)
Time Frame	0 to 120 hours after the initiation of chemotherapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Placebo	APD403 10MG	APD403 20MG	ADP403 40MG
Arm/Group Description	ACUTE (day 1): IV OND + FOS + DEX • DELAYED (days 2 to 4): Oral DEX	ACUTE (day 1): IV OND + APD403 20 mg DELAYED (days 2 to 4): Oral Placebo	ACUTE (day 1): IV OND + APD403 20 mg • DELAYED (days 2 to 4): Oral APD403 10 mg	ACUTE (day 1): IV OND + APD403 20 mg • DELAYED (days 2 to 4): Oral APD403 20 mg	ACUTE (day 1): IV OND + APD403 20 mg • DELAYED (days 2 to 4): Oral APD403 40 mg
Measure Participants	66	66	63	68	65
Count of Participants [Participants]	33 50%	11 16.7%	21 33.3%	17 25%	17 26.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, APD403 10MG
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0235
	Comments
	Method	Chi-squared, Corrected
	Comments	1-sided

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, ADP421 20MG
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1651
	Comments
	Method	Chi-squared, Corrected
	Comments	1-sided

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, APD421 40MG
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1332
	Comments
	Method	Chi-squared, Corrected
	Comments	1-sided

Adverse Events

Time Frame	7 Days
Arm/Group Title	Control		Placebo		APD403 10MG		APD403 20MG		ADP403 40MG
Arm/Group Description	ACUTE (day 1): IV OND + FOS + DEX • DELAYED (days 2 to 4): Oral DEX		ACUTE (day 1): IV OND + APD403 20 mg DELAYED (days 2 to 4): Oral Placebo		ACUTE (day 1): IV OND + APD403 20 mg • DELAYED (days 2 to 4): Oral APD403 10 mg		ACUTE (day 1): IV OND + APD403 20 mg • DELAYED (days 2 to 4): Oral APD403 20 mg		ACUTE (day 1): IV OND + APD403 20 mg • DELAYED (days 2 to 4): Oral APD403 40 mg
All Cause Mortality
	Control		Placebo		APD403 10MG		APD403 20MG		ADP403 40MG
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/66 (3%)		0/66 (0%)		0/63 (0%)		0/68 (0%)		0/65 (0%)
Serious Adverse Events
	Control		Placebo		APD403 10MG		APD403 20MG		ADP403 40MG
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/66 (12.1%)		12/66 (18.2%)		2/63 (3.2%)		3/68 (4.4%)		4/65 (6.2%)
Blood and lymphatic system disorders
Febrile Neutropenia	2/66 (3%)	2	0/66 (0%)	0	0/63 (0%)	0	0/68 (0%)	0	0/65 (0%)	0
Pancytopenia	1/66 (1.5%)	1	0/66 (0%)	0	0/63 (0%)	0	0/68 (0%)	0	0/65 (0%)	0
Cardiac disorders
Cardiac arrest	1/66 (1.5%)	1	0/66 (0%)	0	0/63 (0%)	0	0/68 (0%)	0	0/65 (0%)	0
Gastrointestinal disorders
Nausea	1/66 (1.5%)	1	4/66 (6.1%)	4	1/63 (1.6%)	1	1/68 (1.5%)	1	0/65 (0%)	0
Vomiting	1/66 (1.5%)	1	1/66 (1.5%)	1	0/63 (0%)	0	1/68 (1.5%)	1	0/65 (0%)	0
Duodenal Obstruction	1/66 (1.5%)	1	0/66 (0%)	0	0/63 (0%)	0	0/68 (0%)	0	0/65 (0%)	0
General disorders
Chest Pain	0/66 (0%)	0	1/66 (1.5%)	1	0/63 (0%)	0	0/68 (0%)	0	1/65 (1.5%)	1
Pyrexia	0/66 (0%)	0	2/66 (3%)	2	0/63 (0%)	0	0/68 (0%)	0	0/65 (0%)	0
Infections and infestations
Urinary Tract Infection	0/66 (0%)	0	1/66 (1.5%)	1	0/63 (0%)	0	0/68 (0%)	0	0/65 (0%)	0
Neutropenic sepsis	1/66 (1.5%)	1	0/66 (0%)	0	0/63 (0%)	0	0/68 (0%)	0	2/65 (3.1%)	2
Injury, poisoning and procedural complications
Infusion related reaction	1/66 (1.5%)	1	0/66 (0%)	0	0/63 (0%)	0	0/68 (0%)	0	0/65 (0%)	0
Investigations
Electrocardiogram QT Prolonged	0/66 (0%)	0	0/66 (0%)	0	0/63 (0%)	0	1/68 (1.5%)	1	0/65 (0%)	0
Blood Creatine Increase	0/66 (0%)	0	0/66 (0%)	0	0/63 (0%)	0	1/68 (1.5%)	1	0/65 (0%)	0
Blood Prolactin Increased	1/66 (1.5%)	1	1/66 (1.5%)	1	0/63 (0%)	0	0/68 (0%)	0	0/65 (0%)	0
General Physical Condition Abnormal	0/66 (0%)	0	1/66 (1.5%)	1	0/63 (0%)	0	0/68 (0%)	0	0/65 (0%)	0
Nervous system disorders
Dizziness	0/66 (0%)	0	1/66 (1.5%)	1	0/63 (0%)	0	0/68 (0%)	0	0/65 (0%)	0
Psychiatric disorders
Nervousness	0/66 (0%)	0	1/66 (1.5%)	1	0/63 (0%)	0	0/68 (0%)	0	0/65 (0%)	0
Renal and urinary disorders
Renal Failure	0/66 (0%)	0	1/66 (1.5%)	1	1/63 (1.6%)	1	0/68 (0%)	0	0/65 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism	0/66 (0%)	0	0/66 (0%)	0	0/63 (0%)	0	0/68 (0%)	0	1/65 (1.5%)	1
Haemoptysis	1/66 (1.5%)	1	0/66 (0%)	0	0/63 (0%)	0	0/68 (0%)	0	0/65 (0%)	0
Dyspnoea	1/66 (1.5%)	1	0/66 (0%)	0	0/63 (0%)	0	0/68 (0%)	0	0/65 (0%)	0
Other (Not Including Serious) Adverse Events
	Control		Placebo		APD403 10MG		APD403 20MG		ADP403 40MG
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/66 (54.5%)		47/66 (71.2%)		34/63 (54%)		21/68 (30.9%)		28/65 (43.1%)
Gastrointestinal disorders
Constipation	4/66 (6.1%)	4	5/66 (7.6%)	5	7/63 (11.1%)	7	2/68 (2.9%)	2	2/65 (3.1%)	2
Diarrhoea	4/66 (6.1%)	4	6/66 (9.1%)	7	3/63 (4.8%)	3	2/68 (2.9%)	3	2/65 (3.1%)	2
Nausea	2/66 (3%)	2	4/66 (6.1%)	4	1/63 (1.6%)	1	1/68 (1.5%)	1	0/65 (0%)	0
Dyspepsia	2/66 (3%)	2	4/66 (6.1%)	4	0/63 (0%)	0	0/68 (0%)	0	1/65 (1.5%)	1
General disorders
Fatigue	13/66 (19.7%)	13	13/66 (19.7%)	13	13/63 (20.6%)	13	5/68 (7.4%)	5	11/65 (16.9%)	11
Pyrexia	2/66 (3%)	2	4/66 (6.1%)	4	0/63 (0%)	0	1/68 (1.5%)	1	0/65 (0%)	0
Mucosal Dryness	1/66 (1.5%)	1	1/66 (1.5%)	1	1/63 (1.6%)	1	3/68 (4.4%)	3	4/65 (6.2%)	4
Metabolism and nutrition disorders
Decreased Appetite	4/66 (6.1%)	4	2/66 (3%)	2	2/63 (3.2%)	2	4/68 (5.9%)	4	0/65 (0%)	0
Nervous system disorders
Headache	4/66 (6.1%)	4	9/66 (13.6%)	9	7/63 (11.1%)	7	3/68 (4.4%)	3	8/65 (12.3%)	8

Limitations/Caveats

There were no limitations and caveats with this study

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.