GI-NETorPNET: A Ph 2 Study of Fosbretabulin in Subjects w Pancreatic or Gastrointestinal Neuroendocrine Tumors w Elevated Biomarkers

• Sponsor: Mateon Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02132468
• Collaborator: (none)
• Enrollment: 18
• Locations: 5
• Arm: 1
• Duration (Months): 23
• Patients Per Site: 3.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study will investigate the safety, symptoms and biomarker response of subjects with biopsy-proven well-differentiated, low-to-intermediate-grade, unresectable, or metastatic pancreatic neuroendocrine tumors (PNETs) or or Gastrointestinal Neuroendocrine tumors (GI-NETs) with elevated biochemical markers who have relapsed during or after receiving prior standard of care therapies, including octreotide, chemotherapy or targeted therapy.

Condition or Disease	Intervention/Treatment	Phase
Neuroendocrine Tumors	Drug: fosbretabulin tromethamine	Phase 2

Detailed Description

Subjects enrolled in this PNET/GI-NET study (OX4218s) will receive weekly dosing with fosbretabulin for up to 3 cycles or approximately 9 weeks.

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 Ph 2 Study to Investigate the Safety and Activity of Fosbretabulin Tromethamine (CA4P) in the Treatment of Well-Differentiated, Low-to-Intermediate-Grade Unresectable, Recurrent or Metastatic PNET or GI-NET Neuroendocrine Tumors/Carcinoid With Elevated Biomarkers
• Study Start Date: Sep 1, 2014
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Aug 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: fosbretabulin tromethamine Fosbretabulin 90 mg/vial; 60 mg/m2, IV infusion over 10 minutes; 1x/wk; three 3-week cycles	Drug: fosbretabulin tromethamine; 60 mg/m2, IV on Day 1, 8 and 15 of a 3-week cycle; 3 cycles or until progression or unacceptable toxicity; Other Names: fosbretabulin, combretastatin A4-phosphate, CA4P

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Improved, Stable, or Worsened Change In Chromogranin A (CgA) Biomarker Levels From Baseline [Baseline and 4 months]

   The mean change from baseline in chromogranin A (CgA) biomarker level is considered improved if a 25% reduction occurs and worsened if the mean change from baseline is increased by 25%.

2. Number of Participants With Improved, Stable, or Worsened Change In 5-hydroxyindoleacetic Acid (5-HIAA) Biomarker Levels From Baseline [Baseline and 4 months]

   The mean change from baseline in 5-hydroxyindoleacetic acid (5-HIAA) biomarker level is considered improved if a 25% reduction occurs and worsened if the mean change from baseline is increased by 25%.

3. Number of Participants With Improved, Stable, or Worsened Change In Serotonin Biomarker Levels From Baseline [Baseline and 4 months]

   The mean change from baseline in serotonin biomarker level is considered improved if a 25% reduction occurs and worsened if the mean change from baseline is increased by 25%.

Secondary Outcome Measures

1. Number of Participants With Partial Response (PR), Progressive Disease (PD), or Stable Disease (SD) Based on RECIST 1.1 [Baseline and 4 months]

   The objective response rate (complete response, partial response, progressive disease, or stable disease) was determined by the investigator assessment of the participant's CT or MRI using Response Evaluation Criteria in Solid Tumors Criteria (RECIST 1.1) for target lesions. Partial Response (PR) is when there is at least 30% decrease in sum of the longest diameter of the target lesions. Progressive Disease (PD) is when there is at least 20% increase in the sum of the longest diameter of the target lesions, as well as an absolute increase of at least 5 mm (including appearance of new lesions). Stable Disease (SD) is when there neither a PR nor PD is noted.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Ability to read, understand and provide written consent to participate in the study

• Age ≥ 18 years

• Biopsy-proven well-differentiated, low-to-intermediate-grade PNET or GI-NET with elevated (> ULN) biomarkers (serotonin, 5-hydroxyindoleacetic acid (5-HIAA), chromogranin A (CgA), neurokinin A, and neuron-specific enolase (NSE))

• Life expectancy > 12 weeks

• Must have received or may still be receiving one or more therapies including octreotide or serotonin synthesis inhibitor (SSI) or other somatostatin analogues

• Confirmed progressive disease within 18 months of enrollment on study

• Recovered from prior radiation therapy or surgery

• Eastern Cooperative Oncology Group (ECOG) performance score 0-2

• Absolute neutrophil count (ANC) ≥ 1,500/µL (without growth factors)

• Platelet count ≥ 100,000/µL

• Adequate renal function as evidenced by serum creatinine

≤ 2.0 mg/dL (177 µmol/L)

• Adequate hepatic function: serum total bilirubin ≤ 2X greater than the upper limit of normal (ULN) (≤ 3X ULN in subjects with liver metastases), aspartate aminotransferase) AST) / alanine aminotransferase (AST) ≤ 2X the ULN for the local reference lab (≤ 5X the ULN for subjects with liver metastases)

• Disease that can be assessed (evaluable) with imaging (CT, MRI, PET, radionuclide imaging or other imaging modality)

• Women of childbearing potential as well as fertile men and their partners must use an effective method of birth control

Exclusion Criteria:

• Inadequately controlled hypertension defined as BP > 150/100 mm Hg despite medication

• Prior history of hypertensive crisis or hypertensive encephalopathy

• Recent history (within 6 months of start of screening) of unstable angina pectoris pattern, myocardial infarction (including non-Q wave MI), or NYHA (New York Heart Association) Class III and IV Congestive Heart Failure (CHF)

• Subjects who have clinical evidence of carcinoid-induced heart disease

• History of prior cerebrovascular accident (CVA), including transient ischemic attach (TIA)

• Known central nervous system (CNS) disease except for treated brain metastasis

• History of torsade de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia (<60 bpm), heart block (excluding 1st degree block, being PR interval prolongation only), congenital long QT syndrome or new ST segment elevation or depression or new Q wave on ECG

• Corrected QT interval (QTc) > 480 msec

• Ongoing treatment with any drugs known to prolong the QTc interval, including anti-arrhythmic medications (stable regimen of antidepressants of the selective serotonin reuptake inhibitor (SSRI) class is allowed))

• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)

• Significant vascular disease or recent peripheral arterial thrombosis

• Known intolerance of or hypersensitivity to fosbretabulin

• History of solid organ transplant or bone marrow transplant

• Any other intercurrent medical condition, including mental illness or substance abuse, deemed by the Investigator to be likely to interfere with a subject's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results

• High grade or poorly differentiated NET

• NET tumor other than PNET or GI-NET

• No elevated biomarker (>ULN) that can be followed

• Received regional hepatic infusion therapy within 6 months of enrollment (RFA allowed

6 months prior to enrollment)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University School of Medicine	Stanford	California	United States	94305
2	Markey Cancer Center, Clinical Research Office	Lexington	Kentucky	United States	40356
3	Montefiore	Bronx	New York	United States	10467
4	Duke University Medical Center	Durham	North Carolina	United States	27710
5	Froedtert Hospital, Medicial College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Mateon Therapeutics

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mateon Therapeutics
• ClinicalTrials.gov Identifier: NCT02132468
• Other Study ID Numbers: OX4218s
• First Posted: May 7, 2014
• Last Update Posted: Dec 5, 2017
• Last Verified: Oct 1, 2017

• Keywords provided by Mateon Therapeutics: PNET; GI-NET; neuroendocrine; carcinoid
• Additional relevant MeSH terms: Neuroendocrine Tumors; Fosbretabulin; Combretastatin

Study Results

Participant Flow

Arm/Group Title	Fosbretabulin Tromethamine
Arm/Group Description	Fosbretabulin 90 mg/vial; 60 mg/m2, IV infusion over 10 minutes; 1x/wk; three 3-week cycles fosbretabulin tromethamine: 60 mg/m2, IV on Day 1, 8 and 15 of a 3-week cycle; 3 cycles or until progression or unacceptable toxicity
Period Title: Overall Study
STARTED	18
COMPLETED	11
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Fosbretabulin Tromethamine
Arm/Group Description	Fosbretabulin 90 mg/vial; 60 mg/m2, IV infusion over 10 minutes; 1x/wk; three 3-week cycles fosbretabulin tromethamine: 60 mg/m2, IV on Day 1, 8 and 15 of a 3-week cycle; 3 cycles or until progression or unacceptable toxicity
Overall Participants	18
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.8 (9.28)
Sex: Female, Male (Count of Participants)
Female	9 50%
Male	9 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 11.1%
White	16 88.9%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Improved, Stable, or Worsened Change In Chromogranin A (CgA) Biomarker Levels From Baseline
Description	The mean change from baseline in chromogranin A (CgA) biomarker level is considered improved if a 25% reduction occurs and worsened if the mean change from baseline is increased by 25%.
Time Frame	Baseline and 4 months

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Fosbretabulin Tromethamine
Arm/Group Description	Fosbretabulin 90 mg/vial; 60 mg/m2, IV infusion over 10 minutes; 1x/wk; three 3-week cycles fosbretabulin tromethamine: 60 mg/m2, IV on Day 1, 8 and 15 of a 3-week cycle; 3 cycles or until progression or unacceptable toxicity
Measure Participants	18
Improved	1 5.6%
Stable	11 61.1%
Worsened	6 33.3%

2. Primary Outcome

Title	Number of Participants With Improved, Stable, or Worsened Change In 5-hydroxyindoleacetic Acid (5-HIAA) Biomarker Levels From Baseline
Description	The mean change from baseline in 5-hydroxyindoleacetic acid (5-HIAA) biomarker level is considered improved if a 25% reduction occurs and worsened if the mean change from baseline is increased by 25%.
Time Frame	Baseline and 4 months

Outcome Measure Data

Analysis Population Description

Participants who had 5-hydroxyindoleacetic acid (5-HIAA) biomaker sample taken at baseline and at 4 months.

Arm/Group Title	Fosbretabulin Tromethamine
Arm/Group Description	Fosbretabulin 90 mg/vial; 60 mg/m2, IV infusion over 10 minutes; 1x/wk; three 3-week cycles fosbretabulin tromethamine: 60 mg/m2, IV on Day 1, 8 and 15 of a 3-week cycle; 3 cycles or until progression or unacceptable toxicity
Measure Participants	13
Improved	2 11.1%
Stable	8 44.4%
Worsened	3 16.7%

3. Primary Outcome

Title	Number of Participants With Improved, Stable, or Worsened Change In Serotonin Biomarker Levels From Baseline
Description	The mean change from baseline in serotonin biomarker level is considered improved if a 25% reduction occurs and worsened if the mean change from baseline is increased by 25%.
Time Frame	Baseline and 4 months

Outcome Measure Data

Analysis Population Description

Participants who had serotonin biomaker samples taken at baseline and at 4 months.

Arm/Group Title	Fosbretabulin Tromethamine
Arm/Group Description	Fosbretabulin 90 mg/vial; 60 mg/m2, IV infusion over 10 minutes; 1x/wk; three 3-week cycles fosbretabulin tromethamine: 60 mg/m2, IV on Day 1, 8 and 15 of a 3-week cycle; 3 cycles or until progression or unacceptable toxicity
Measure Participants	12
Improved	0 0%
Stable	10 55.6%
Worsened	2 11.1%

4. Secondary Outcome

Title	Number of Participants With Partial Response (PR), Progressive Disease (PD), or Stable Disease (SD) Based on RECIST 1.1
Description	The objective response rate (complete response, partial response, progressive disease, or stable disease) was determined by the investigator assessment of the participant's CT or MRI using Response Evaluation Criteria in Solid Tumors Criteria (RECIST 1.1) for target lesions. Partial Response (PR) is when there is at least 30% decrease in sum of the longest diameter of the target lesions. Progressive Disease (PD) is when there is at least 20% increase in the sum of the longest diameter of the target lesions, as well as an absolute increase of at least 5 mm (including appearance of new lesions). Stable Disease (SD) is when there neither a PR nor PD is noted.
Time Frame	Baseline and 4 months

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat

Arm/Group Title	Fosbretabulin Tromethamine
Arm/Group Description	Fosbretabulin 90 mg/vial; 60 mg/m2, IV infusion over 10 minutes; 1x/wk; three 3-week cycles fosbretabulin tromethamine: 60 mg/m2, IV on Day 1, 8 and 15 of a 3-week cycle; 3 cycles or until progression or unacceptable toxicity
Measure Participants	14
Partial Response	1 5.6%
Stable Disease	7 38.9%
Progressive Disease	6 33.3%

Adverse Events

Time Frame	1 year
Arm/Group Title	Fosbretabulin Tromethamine
Arm/Group Description	Fosbretabulin 90 mg/vial; 60 mg/m2, IV infusion over 10 minutes; 1x/wk; three 3-week cycles fosbretabulin tromethamine: 60 mg/m2, IV on Day 1, 8 and 15 of a 3-week cycle; 3 cycles or until progression or unacceptable toxicity
All Cause Mortality
	Fosbretabulin Tromethamine
	Affected / at Risk (%)	# Events
Total	1/18 (5.6%)
Serious Adverse Events
	Fosbretabulin Tromethamine
	Affected / at Risk (%)	# Events
Total	2/18 (11.1%)
Endocrine disorders
Carcinoid Syndrome	1/18 (5.6%)
Infections and infestations
Pneumonia	1/18 (5.6%)
Urosepsis	1/18 (5.6%)
Other (Not Including Serious) Adverse Events
	Fosbretabulin Tromethamine
	Affected / at Risk (%)	# Events
Total	18/18 (100%)
Blood and lymphatic system disorders
Anaemia	4/18 (22.2%)
Leukaemoid reaction	1/18 (5.6%)
Leukopenia	1/18 (5.6%)
Thrombocytopenia	1/18 (5.6%)
Cardiac disorders
Palpitations	1/18 (5.6%)
Ear and labyrinth disorders
Tinnitus	1/18 (5.6%)
Endocrine disorders
Carcinoid Syndrome	1/18 (5.6%)
Eye disorders
Conjunctivitis Allergic	1/18 (5.6%)
Macular fibrosis	1/18 (5.6%)
vision blurred	1/18 (5.6%)
Gastrointestinal disorders
abdominal discomfort	1/18 (5.6%)
abdominal distension	1/18 (5.6%)
abdominal pain	7/18 (38.9%)
abdominal pain upper	1/18 (5.6%)
anal pruritus	1/18 (5.6%)
ascites	1/18 (5.6%)
constipation	3/18 (16.7%)
diarrhoea	4/18 (22.2%)
dyspepsia	1/18 (5.6%)
epigastric discomfort	1/18 (5.6%)
flatulence	2/18 (11.1%)
eructation	1/18 (5.6%)
frequent bowel movements	2/18 (11.1%)
gastrointestinal pain	1/18 (5.6%)
gastrooesophageal reflux disease	1/18 (5.6%)
hypoaesthesia oral	1/18 (5.6%)
nausea	6/18 (33.3%)
vomiting	4/18 (22.2%)
General disorders
breakthrough pain	1/18 (5.6%)
chest pain	2/18 (11.1%)
chills	3/18 (16.7%)
early satiety	1/18 (5.6%)
fatigue	11/18 (61.1%)
feeling jittery	1/18 (5.6%)
injection site bruising	1/18 (5.6%)
local swelling	1/18 (5.6%)
non-cardiac chest pain	1/18 (5.6%)
oedema peripheral	4/18 (22.2%)
pyrexia	4/18 (22.2%)
Hepatobiliary disorders
hepatic failure	1/18 (5.6%)
Infections and infestations
Oral herpes	1/18 (5.6%)
Pneumonia	1/18 (5.6%)
upper respiratory tract infection	1/18 (5.6%)
urinary tract infection	5/18 (27.8%)
urosepsis	1/18 (5.6%)
Injury, poisoning and procedural complications
infusion related reaction	3/18 (16.7%)
upper limb fracture	1/18 (5.6%)
Investigations
alanine aminotransferase increased	6/18 (33.3%)
aspartate aminotransferase increased	6/18 (33.3%)
blood alkaline phosphatase increased	3/18 (16.7%)
blood creatinine increased	1/18 (5.6%)
blood magnesium increased	1/18 (5.6%)
weight decreased	1/18 (5.6%)
white blood cell count increased	1/18 (5.6%)
Metabolism and nutrition disorders
decreased appetite	3/18 (16.7%)
dehydration	2/18 (11.1%)
diabetes mellitus	1/18 (5.6%)
hyperglycemia	1/18 (5.6%)
hyperkalaemia	1/18 (5.6%)
hypoalbuminaemia	3/18 (16.7%)
hypocalcaemia	1/18 (5.6%)
hypokalaemia	3/18 (16.7%)
hypomagnesaemia	3/18 (16.7%)
hypophosphataemia	1/18 (5.6%)
hypovolaemia	1/18 (5.6%)
metabolic acidosis	1/18 (5.6%)
Musculoskeletal and connective tissue disorders
arthralgia	1/18 (5.6%)
back pain	7/18 (38.9%)
bone pain	2/18 (11.1%)
connective tissue disorder	1/18 (5.6%)
flank pain	3/18 (16.7%)
muscle spasms	1/18 (5.6%)
muscular weakness	1/18 (5.6%)
musculoskeletal pain	1/18 (5.6%)
myalgia	1/18 (5.6%)
neck pain	2/18 (11.1%)
pain in jaw	1/18 (5.6%)
Nervous system disorders
cranial nerve disorder	1/18 (5.6%)
dizziness	1/18 (5.6%)
encephalopathy	1/18 (5.6%)
headache	3/18 (16.7%)
migraine	1/18 (5.6%)
neuralgia	1/18 (5.6%)
neuropathy peripheral	3/18 (16.7%)
paraesthesia	4/18 (22.2%)
restless leg syndrome	2/18 (11.1%)
tremor	1/18 (5.6%)
Psychiatric disorders
anxiety	1/18 (5.6%)
depression	1/18 (5.6%)
Renal and urinary disorders
dysuria	1/18 (5.6%)
polyuria	1/18 (5.6%)
proteinuria	1/18 (5.6%)
renal failure	1/18 (5.6%)
renal failure acute	1/18 (5.6%)
urinary retention	1/18 (5.6%)
Reproductive system and breast disorders
prostatitis	1/18 (5.6%)
pruritis genital	1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
cough	2/18 (11.1%)
dysphonia	1/18 (5.6%)
dyspnoea	4/18 (22.2%)
dyspnoea exertional	1/18 (5.6%)
hypoxia	1/18 (5.6%)
respiratory failure	1/18 (5.6%)
Skin and subcutaneous tissue disorders
blister	1/18 (5.6%)
hyperhydrosis	1/18 (5.6%)
night sweats	5/18 (27.8%)
pruritis	5/18 (27.8%)
pruritis generalised	1/18 (5.6%)
rash	2/18 (11.1%)
rosacea	1/18 (5.6%)
Vascular disorders
flushing	4/18 (22.2%)
hypertension	3/18 (16.7%)
hypotension	4/18 (22.2%)

Limitations/Caveats

[Not Specified]

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.