Avatrombopag for the Treatment of Chemotherapy-Induced Thrombocytopenia in Adults With Active Non-Hematological Cancers

• Sponsor: Sobi, Inc. (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03471078
• Collaborator: (none)
• Enrollment: 122
• Locations: 55
• Arms: 2
• Anticipated Duration (Months): 81.6
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of avatrombopag in subjects with chemotherapy-induced thrombocytopenia receiving chemotherapy for the treatment of ovarian, lung (small cell and non-small cell) and bladder cancer.

Condition or Disease	Intervention/Treatment	Phase
Chemotherapy-induced Thrombocytopenia	Drug: Avatrombopag; Drug: Placebo Oral Tablet	Phase 3

Detailed Description

Subjects will receive placebo controlled test treatment for one cycle of chemotherapy followed by an observational cycle. Subjects will have the option to continue into an open label extension period for all remaining chemotherapy cycles within the current regimen. After the follow-up visit, all subjects will continue to a long-term safety follow-up period.

Study Design

• Study Type: Interventional
• Actual Enrollment: 122 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Supportive Care
• Official Title: Randomized, Double-Blind, Placebo-Controlled Study With Open-Label Extension to Evaluate the Efficacy and Safety of Avatrombopag for the Treatment of Chemotherapy-Induced Thrombocytopenia in Subjects With Active Non-Hematological Cancers
• Actual Study Start Date: Oct 12, 2018
• Actual Primary Completion Date: Aug 28, 2020
• Anticipated Study Completion Date: Aug 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Avatrombopag Study is 2:1 randomization ratio (avatrombopag to placebo). Investigational product administered orally once daily for 5 days prior to chemotherapy and 5 days following chemotherapy treatment.	Drug: Avatrombopag; Oral avatrombopag tablet
Placebo Comparator: Placebo Study is 2:1 randomization ratio (avatrombopag to placebo). Investigational product administered orally once daily for 5 days prior to chemotherapy and 5 days following chemotherapy treatment.	Drug: Placebo Oral Tablet; Placebo comparator tablet

Outcome Measures

Primary Outcome Measures

1. Percentage of Subjects Who do Not Require Platelet Transfusion, Dose Reduction in Chemotherapy by 15%, or Chemotherapy Delay by >=4 Days [Randomization up to 33 days]

Secondary Outcome Measures

1. Duration of Severe Thrombocytopenia Defined as a Platelet Count <50 x 10^9/L [Randomization up to 33 days]

   The duration of severe thrombocytopenia is defined as the total number of days with a platelet count <50×10^9/L during the period after post-chemotherapy study drug treatment in Cycle X+1 through Chemotherapy Day of Cycle X+2.

2. Change in Platelet Count From Baseline (Nadir) [Randomization up to 33 days]

   Comparison of avatrombopag 60 mg vs. placebo, adjusted for the number of chemotherapy agents currently receiving per IWRS (1, ≥2). Cycle X nadir is defined as the lowest platelet count value prior to the first dose of study drug; Cycle X+1 nadir is defined as the lowest platelet count value during the period after post-chemotherapy study drug treatment in Cycle X+1 through Chemotherapy Day in Cycle X+2.

3. Percentage of Subjects Who Did Not Have Major or Non-major Clinically Relevant Bleeding During the Period After Post-chemotherapy Study Drug Treatment in Cycle X+1 Through Chemotherapy Day of Cycle X+2. [Randomization up to 33 days]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Men and women greater than or equal to 18 years of age;

• A diagnosis of ovarian, lung (small cell or non-small cell) or bladder cancer requiring systemic chemotherapy

• Participant receiving a chemotherapy regimen given in a 21 or 28-day cycle, including 1 or more of the following agents or class of agents:

• Nucleoside analog, including gemcitabine and fluorouracil;

• Carboplatin or cisplatin;

• Anthracycline; or

• Alkylating agent;

• Participant experienced severe thrombocytopenia, defined as 2 platelet counts <50 x 109/L measured at least 24 hours apart, during the qualifying chemotherapy cycle, of their current chemotherapy regimen

• ECOG performance status <=2

Exclusion Criteria:

• Participant has experienced >=Grade 2 CIT other than during the current chemotherapy treatment regimen within 6 months of Screening;

• Participant has any history of hematologic malignancies, including leukemia, myeloma, myeloproliferative disease, lymphoma, or myelodysplastic diseases;

• Participant has received >2 previous lines of chemotherapy or is receiving whole brain radiation during the study treatment period;

• Participant has a known medical history of genetic prothrombotic syndromes

• Participant has a history of arterial or venous thrombosis within 3 months of screening;

• Use of vitamin K antagonists;

• Participant has previously received a thrombopoietin receptor agonist or recombinant human thrombopoietin for the treatment of CIT within 3 months of screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dova Site	Anaheim	California	United States	92801
2	Dova Site	Bakersfield	California	United States	93309
3	Dova Site	Riverside	California	United States	92501
4	Dova Site	Santa Monica	California	United States	90403
5	Dova Site	Augusta	Georgia	United States	30912
6	Dova Site	Harvey	Illinois	United States	60426
7	Dova Site	Skokie	Illinois	United States	60076
8	Dova Site	Bloomington	Indiana	United States	47403
9	Dova Site	Wichita	Kansas	United States	67214
10	Dova Site	Ashland	Kentucky	United States	41101
11	Dova Site	Boston	Massachusetts	United States	02114
12	Dova Site	Minneapolis	Minnesota	United States	55417
13	Dova Site	Canton	Ohio	United States	44718
14	Dova Site	Gettysburg	Pennsylvania	United States	17325
15	Dova Site	Harbin		China
16	Dova Site	Linyi		China
17	Dova Site	Neijiang		China
18	Dova Site	Shanghai		China
19	Dova Site	Tianjin		China
20	Dova Site	Budapest		Hungary
21	Dova Site	Debrecen		Hungary
22	Dova Site	Nyiregyhaza		Hungary
23	Dova Site	Törökbálint		Hungary
24	Dova Site	Lublin		Poland
25	Dova Site	Olsztyn		Poland
26	Dova Site	Prabuty		Poland
27	Dova Site	Tomaszów Mazowiecki		Poland
28	Dova Site	Warsaw		Poland
29	Dova Site	Arkhangel'sk		Russian Federation
30	Dova Site	Kazan		Russian Federation
31	Dova Site	Kursk		Russian Federation
32	Dova Site	Moscow		Russian Federation
33	Dova Site	Novosibirsk		Russian Federation
34	Dova Site	Omsk		Russian Federation
35	Dova Site	Pyatigorsk		Russian Federation	357502
36	Dova Site	Saint Petersburg		Russian Federation	188663
37	Dova Site	Saint Petersburg		Russian Federation
38	Dova Site	Saransk		Russian Federation
39	Dova Site	Sochi		Russian Federation
40	Dova Site	Belgrade		Serbia
41	Dova Site	Kragujevac		Serbia
42	Dova Site	Sremska Kamenica		Serbia
43	Dova Site	Cherkasy		Ukraine
44	Dova Site	Chernihiv		Ukraine
45	Dova Site	Chernivtsi		Ukraine
46	Dova Site	Ivano-Frankivs'k		Ukraine
47	Dova Site	Kharkiv		Ukraine
48	Dova Site	Kherson		Ukraine
49	Dova Site	Kropyvnytskyi		Ukraine
50	Dova Site	Kyiv		Ukraine
51	Dova Site	Odesa		Ukraine
52	Dova Site	Sumy		Ukraine
53	Dova Site	Ternopil'		Ukraine
54	Dova Site	Uzhhorod		Ukraine
55	Dova Site	Vinnytsia		Ukraine

Sponsors and Collaborators

• Sobi, Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Apr 4, 2019
• Statistical Analysis Plan - Aug 31, 2020

More Information

Publications

None provided.

• Responsible Party: Sobi, Inc.
• ClinicalTrials.gov Identifier: NCT03471078
• Other Study ID Numbers: AVA-CIT-330
• First Posted: Mar 20, 2018
• Last Update Posted: Nov 24, 2021
• Last Verified: Nov 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Sobi, Inc.: CIT; Thrombocytopenia
• Additional relevant MeSH terms: Thrombocytopenia

Study Results

Participant Flow

Recruitment Details	This was a Phase 3, randomized, double- blind, placebo controlled study of the efficacy and and safety of avatrombopag in subjects with chemotherapy induced thrombocytopenia and non active non-hematologic cancers. The study was conducted by qualified investigators at 71 sites in China, Hungary, Poland, Russia, Serbia, Ukraine, and the United States. The first subject was enrolled 12October2018.
Pre-assignment Detail	The study was conducted by qualified investigators at 71 sites in China, Hungary, Poland, Russia, Serbia, Ukraine, and the United States. The first subject was enrolled 12October2018.

Arm/Group Title	Avatrombopag	Placebo
Arm/Group Description	Study is 2:1 randomization ratio (avatrombopag to placebo). 60 mg of Investigational product administered orally once daily for 5 days prior to chemotherapy and 5 days following chemotherapy treatment. Avatrombopag: Oral avatrombopag tablet	Study is 2:1 randomization ratio (avatrombopag to placebo). 60 mg Investigational product administered orally once daily for 5 days prior to chemotherapy and 5 days following chemotherapy treatment. Placebo Oral Tablet: Placebo comparator tablet
Period Title: Overall Study
STARTED	82	40
COMPLETED	61	34
NOT COMPLETED	21	6

Baseline Characteristics

Arm/Group Title	Avatrombopag	Placebo	Total
Arm/Group Description	Study is 2:1 randomization ratio (avatrombopag to placebo). Investigational product administered orally once daily for 5 days prior to chemotherapy and 5 days following chemotherapy treatment. Avatrombopag: Oral avatrombopag tablet	Study is 2:1 randomization ratio (avatrombopag to placebo). Investigational product administered orally once daily for 5 days prior to chemotherapy and 5 days following chemotherapy treatment. Placebo Oral Tablet: Placebo comparator tablet	Total of all reporting groups
Overall Participants	82	40	122
Age (years) [Mean (Standard Deviation) ]
Age at Enrollment	61.0 (10.08)	60.8 (10.41)	61.0 (10.15)
Sex: Female, Male (Count of Participants)
Female	43 52.4%	22 55%	65 53.3%
Male	39 47.6%	18 45%	57 46.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	78 95.1%	37 92.5%	115 94.3%
Unknown or Not Reported	4 4.9%	3 7.5%	7 5.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	5 6.1%	3 7.5%	8 6.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	77 93.9%	37 92.5%	114 93.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
ECOG Performance Status (Count of Participants)
Subjects with ECOG Score 0	21 25.6%	8 20%	29 23.8%
Subjects with ECOG Score 1	60 73.2%	31 77.5%	91 74.6%
Subjects with ECOG Score 2	1 1.2%	1 2.5%	2 1.6%
Number of Eligible Chemotherapy Agents Currently Receiving per IWRS (Count of Participants)
Subjects Receiving 1 Agent	40 48.8%	20 50%	60 49.2%
Subjects Receiving ≥ 2 Agents	42 51.2%	20 50%	62 50.8%
Baseline Platelet Count (x10⁹/L) (platelets x10⁹/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [platelets x10⁹/L]	29.6 (13.66)	33.0 (11.49)	30.7 (13.04)
Height (cm) (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	166.3 (10.17)	166.2 (10.32)	166.3 (10.18)
Weight (kg) (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	76.2 (17.73)	78.8 (17.64)	77.0 (17.67)
BMI (kg/m²) (kg/m²) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m²]	27.7 (6.56)	28.5 (5.58)	27.9 (6.24)

Outcome Measures

1. Primary Outcome

Title	Percentage of Subjects Who do Not Require Platelet Transfusion, Dose Reduction in Chemotherapy by 15%, or Chemotherapy Delay by >=4 Days
Time Frame	Randomization up to 33 days

Outcome Measure Data

Analysis Population Description

All randomized subjects

Arm/Group Title	Avatrombopag	Placebo
Arm/Group Description	Avatrombopag: Oral avatrombopag tablet	Placebo Oral Tablet: Placebo comparator tablet
Measure Participants	82	40
Count of Participants [Participants]	57 69.5%	29 72.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Avatrombopag, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The primary efficacy endpoint was tested between avatrombopag and placebo using the Cochran-Mantel-Haenszel 2-sided test at α=0.05, adjusting for the number of eligible chemotherapy agents as collected in IWRS (1 or ≥2 permissible chemotherapy agents).
Statistical Test of Hypothesis	p-Value	0.7186
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.0
	Confidence Interval	(2-Sided) 95%; -21.7 to 15.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Duration of Severe Thrombocytopenia Defined as a Platelet Count <50 x 10^9/L
Description	The duration of severe thrombocytopenia is defined as the total number of days with a platelet count <50×10^9/L during the period after post-chemotherapy study drug treatment in Cycle X+1 through Chemotherapy Day of Cycle X+2.
Time Frame	Randomization up to 33 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Avatrombopag	Placebo
Arm/Group Description	Avatrombopag: Oral avatrombopag tablet	Placebo Oral Tablet: Placebo comparator tablet
Measure Participants	81	40
Mean (Standard Deviation) [Days]	4.6 (5.53)	4.7 (6.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Avatrombopag, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8372
	Comments
	Method	Van Elteren Test
	Comments

3. Secondary Outcome

Title	Change in Platelet Count From Baseline (Nadir)
Description	Comparison of avatrombopag 60 mg vs. placebo, adjusted for the number of chemotherapy agents currently receiving per IWRS (1, ≥2). Cycle X nadir is defined as the lowest platelet count value prior to the first dose of study drug; Cycle X+1 nadir is defined as the lowest platelet count value during the period after post-chemotherapy study drug treatment in Cycle X+1 through Chemotherapy Day in Cycle X+2.
Time Frame	Randomization up to 33 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Avatrombopag	Placebo
Arm/Group Description	Avatrombopag: Oral avatrombopag tablet	Placebo Oral Tablet: Placebo comparator tablet
Measure Participants	82	40
Mean (Standard Deviation) [Platelets x 10^9/L]	51.5 (61.85)	29.1 (39.48)

4. Secondary Outcome

Title	Percentage of Subjects Who Did Not Have Major or Non-major Clinically Relevant Bleeding During the Period After Post-chemotherapy Study Drug Treatment in Cycle X+1 Through Chemotherapy Day of Cycle X+2.
Time Frame	Randomization up to 33 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Avatrombopag	Placebo
Arm/Group Description	Avatrombopag: Oral avatrombopag tablet	Placebo Oral Tablet: Placebo comparator tablet
Measure Participants	82	40
Count of Participants [Participants]	82 100%	40 100%

Adverse Events

Time Frame	Adverse event data were collected during the Double-Blind Treatment Phase and included two 21- or 28-day chemotherapy cycles.
Adverse Event Reporting Description	Adverse events were assessed by Investigators at each study visit.
Arm/Group Title	Avatrombopag		Placebo
Arm/Group Description	Avatrombopag: Oral avatrombopag tablet		Placebo Oral Tablet: Placebo comparator tablet
All Cause Mortality
	Avatrombopag		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/82 (2.4%)		0/40 (0%)
Serious Adverse Events
	Avatrombopag		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/82 (19.5%)		8/40 (20%)
Blood and lymphatic system disorders
Thrombocytopenia	4/82 (4.9%)		4/40 (10%)
Pancytopenia	3/82 (3.7%)		0/40 (0%)
Anaemia	1/82 (1.2%)		2/40 (5%)
Febrile neutropenia	1/82 (1.2%)		0/40 (0%)
Leukocytosis	1/82 (1.2%)		0/40 (0%)
Leukopenia	1/82 (1.2%)		1/40 (2.5%)
Neutropenia	0/82 (0%)		2/40 (5%)
Gastrointestinal disorders
Stomatitis	1/82 (1.2%)		0/40 (0%)
Infections and infestations
Pneumonia	1/82 (1.2%)		1/40 (2.5%)
Investigations
Blood lactate dehydrogenase increase	1/82 (1.2%)		0/40 (0%)
Nervous system disorders
Ischaemic cerebral infarction	1/82 (1.2%)		0/40 (0%)
Lacunar infarction	1/82 (1.2%)		0/40 (0%)
Cerebral ischaemia	0/82 (0%)		1/40 (2.5%)
Respiratory, thoracic and mediastinal disorders
Non-small cell lung cancer	1/82 (1.2%)		0/40 (0%)
Vascular disorders
Capillary leak syndrome	1/82 (1.2%)		0/40 (0%)
Other (Not Including Serious) Adverse Events
	Avatrombopag		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	71/82 (86.6%)		36/40 (90%)
Blood and lymphatic system disorders
Anaemia	32/82 (39%)		21/40 (52.5%)
Leukopenia	24/82 (29.3%)		15/40 (37.5%)
Neutropenia	24/82 (29.3%)		17/40 (42.5%)
Thrombocytopenia	15/82 (18.3%)		13/40 (32.5%)
Thombocytosis	9/82 (11%)		2/40 (5%)
Gastrointestinal disorders
Nausea	6/82 (7.3%)		6/40 (15%)
Vomiting	5/82 (6.1%)		0/40 (0%)
General disorders
Asthenia	5/82 (6.1%)		4/40 (10%)
Fatigue	3/82 (3.7%)		3/40 (7.5%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	4/82 (4.9%)		2/40 (5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The disclosure restriction on the PI is that the sponsor will review results communications prior to public release and can embargo communications regarding trial results.