Phase 2 Study of OTL38 for Intra-operative Imaging of Folate Receptor-alpha Positive Ovarian Cancer

• Sponsor: On Target Laboratories, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02317705
• Collaborator: SynteractHCR (Industry)
• Enrollment: 48
• Locations: 4
• Arm: 1
• Duration (Months): 11
• Patients Per Site: 12
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

This study is being done to:

• test the safety of OTL38

• see if OTL38 helps light up the cancer when viewed with the special camera system

• test the safety of the special camera system for use along with OTL38 during surgery

Condition or Disease	Intervention/Treatment	Phase
Ovarian Cancer	Drug: OTL38; Device: Near infrared camera imaging system; Procedure: Laparotomy	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Phase 2, Single Dose, Open-Label Study to Investigate the Safety and Efficacy of OTL38 Injection (OTL38) for Intra-operative Imaging of Folate Receptor-alpha Positive Ovarian Cancer
• Study Start Date: Dec 1, 2014
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Patients Receiving OTL38 All patients in this arm will receive OTL38 for injection and undergo intraoperative imaging.	Drug: OTL38; Other Names: OTL38 for Injection CYTALUX™ (pafolacianine) injection ; Device: Near infrared camera imaging system; Near infrared camera imaging system; Procedure: Laparotomy; primary surgical cytoreduction, interval debulking, or recurrent ovarian cancer surgery

Outcome Measures

Primary Outcome Measures

1. Sensitivity of OTL38 in Detecting Folate Receptor-alpha Positive Ovarian Cancer During Surgery. [Day of Surgery (Day 1)]

   Sensitivity for the detection of folate receptor-alpha positive (FRAP) ovarian cancer lesions is defined as the ratio (multiplied by 100) of the number of FRAO ovarian cancer lesions confirmed by both fluorescent light and the pathology/ and immunohistochemistry lab (TP) over the number of FRAP ovarian cancer lesions confirmed by the pathology/ and immunohistochemistry lab (TP+FN). 95% lower one-sided confidence interval was used.

2. Positive Predictive Value (PPV) of OTL38 in Detecting Folate Receptor-alpha Positive Ovarian Cancer During Surgery. [Day of Surgery (Day 1)]

   PPV for the detection of FRAP ovarian cancer lesions is defined as the ratio (multiplied by 100) of the number of FRAP ovarian cancer lesions confirmed by both fluorescent light and the pathology/ and immunohistochemistry lab (TP) over the number of FRAP ovarian cancer lesions confirmed by fluorescent light (TP + FP). 95% lower one-sided confidence interval was used.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Female patients 18 years of age and older

2. Have a primary diagnosis, or at high clinical suspicion, of primary ovarian cancer (of epithelial type), planned for primary debulking or interval debulking surgery, and:

• Who are scheduled to undergo laparotomy for the debulking surgery OR

• Who are scheduled to undergo laparoscopy and pre-authorized to undergo laparotomy for the debulking surgery, if cancer is detected on the laparoscopy

1. A negative serum pregnancy test at Screening followed by a negative urine pregnancy test on the day of surgery or day of admission for female patients of childbearing potential

2. Female patients of childbearing potential or less than 2 years postmenopausal agree to use an acceptable form of contraception from the time of signing informed consent until 30 days after study completion

3. Ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and to return for the required assessments

Exclusion Criteria:

1. Previous exposure to OTL38

2. Known FR alpha-negative ovarian cancer

3. Planned surgical approach via laparoscopy or robotic surgery

4. Any medical condition that in the opinion of the investigators could potentially jeopardize the safety of the patient

5. History of anaphylactic reactions or severe allergies

6. History of allergy to any of the components of OTL38, including folic acid

7. Pregnancy, or positive pregnancy test

8. Clinically significant abnormalities on electrocardiogram (ECG)

9. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

10. Impaired renal function defined as eGFR< 50 mL/min/1.73m2

11. Impaired liver function defined as values > 3x the upper limit of normal (ULN) for alanine aminotransferase (ALT) or aspartate aminotransferase (AST), alkaline phosphatase (ALP), or total bilirubin.

12. Known Stage IV ovarian cancer with Brain Metastases

13. Received an investigational agent in another investigational drug or vaccine trial within 30 days prior to surgery

14. Known sensitivity to fluorescent light

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of CA at Irvine Chao Cancer Center	Orange	California	United States	92868
2	Moffitt Cancer Center	Tampa	Florida	United States	33612
3	Mayo Clinic-Rochester	Rochester	Minnesota	United States	55905
4	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• On Target Laboratories, LLC
• SynteractHCR

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Al Rawahi T, Lopes AD, Bristow RE, Bryant A, Elattar A, Chattopadhyay S, Galaal K. Surgical cytoreduction for recurrent epithelial ovarian cancer. Cochrane Database Syst Rev. 2013 Feb 28;(2):CD008765. doi: 10.1002/14651858.CD008765.pub3. Review.
• Crane LM, Arts HJ, van Oosten M, Low PS, van der Zee AG, van Dam GM, Bart J. The effect of chemotherapy on expression of folate receptor-alpha in ovarian cancer. Cell Oncol (Dordr). 2012 Feb;35(1):9-18. doi: 10.1007/s13402-011-0052-6. Epub 2011 Jun 7. Erratum in: Cell Oncol (Dordr). 2012 Jun;35(3):229.
• Ibeanu OA, Bristow RE. Predicting the outcome of cytoreductive surgery for advanced ovarian cancer: a review. Int J Gynecol Cancer. 2010 Jan;20 Suppl 1:S1-11. doi: 10.1111/IGC.0b013e3181cff38b. Review.
• Kalli KR, Oberg AL, Keeney GL, Christianson TJ, Low PS, Knutson KL, Hartmann LC. Folate receptor alpha as a tumor target in epithelial ovarian cancer. Gynecol Oncol. 2008 Mar;108(3):619-26. doi: 10.1016/j.ygyno.2007.11.020. Epub 2008 Jan 28.
• Leamon CP, Low PS. Membrane folate-binding proteins are responsible for folate-protein conjugate endocytosis into cultured cells. Biochem J. 1993 May 1;291 ( Pt 3):855-60.
• Markert S, Lassmann S, Gabriel B, Klar M, Werner M, Gitsch G, Kratz F, Hasenburg A. Alpha-folate receptor expression in epithelial ovarian carcinoma and non-neoplastic ovarian tissue. Anticancer Res. 2008 Nov-Dec;28(6A):3567-72.
• Parker N, Turk MJ, Westrick E, Lewis JD, Low PS, Leamon CP. Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Anal Biochem. 2005 Mar 15;338(2):284-93.
• Ross JF, Chaudhuri PK, Ratnam M. Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Physiologic and clinical implications. Cancer. 1994 May 1;73(9):2432-43.
• Shih KK, Chi DS. Maximal cytoreductive effort in epithelial ovarian cancer surgery. J Gynecol Oncol. 2010 Jun;21(2):75-80. doi: 10.3802/jgo.2010.21.2.75. Epub 2010 Jun 30.
• Toffoli G, Russo A, Gallo A, Cernigoi C, Miotti S, Sorio R, Tumolo S, Boiocchi M. Expression of folate binding protein as a prognostic factor for response to platinum-containing chemotherapy and survival in human ovarian cancer. Int J Cancer. 1998 Apr 17;79(2):121-6.
• van Dam GM, Themelis G, Crane LM, Harlaar NJ, Pleijhuis RG, Kelder W, Sarantopoulos A, de Jong JS, Arts HJ, van der Zee AG, Bart J, Low PS, Ntziachristos V. Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results. Nat Med. 2011 Sep 18;17(10):1315-9. doi: 10.1038/nm.2472.
• Weitman SD, Lark RH, Coney LR, Fort DW, Frasca V, Zurawski VR Jr, Kamen BA. Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. Cancer Res. 1992 Jun 15;52(12):3396-401.

• Responsible Party: On Target Laboratories, LLC
• ClinicalTrials.gov Identifier: NCT02317705
• Other Study ID Numbers: OTL-2014-OTL38-003
• First Posted: Dec 16, 2014
• Last Update Posted: Jun 21, 2022
• Last Verified: May 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial

Study Results

Participant Flow

Pre-assignment Detail	Subjects were screened up to 28 days prior to surgery.

Arm/Group Title	OTL38 for Intra-operativeImaging of Folate Receptor-alpha Positive Ovarian Cancer
Arm/Group Description	Patient injected with a dose of 0.025 mg/kg OTL38 and undergoes intraoperative imaging
Period Title: Overall Study
STARTED	48
Safety Population	44
Modified Intent-to-Treat (mITT)	29
COMPLETED	43
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	OTL38 for Intra-operative Imaging of Folate Receptor-alpha Positive Ovarian Cancer
Arm/Group Description	Patient injected with a dose of 0.025 mg/kg OTL38 and undergoes intraoperative imaging
Overall Participants	44
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	23 52.3%
>=65 years	21 47.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.8 (10.19)
Sex: Female, Male (Count of Participants)
Female	44 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	37 84.1%
Unknown or Not Reported	7 15.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	3 6.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 2.3%
White	35 79.5%
More than one race	1 2.3%
Unknown or Not Reported	4 9.1%
Region of Enrollment (participants) [Number]
United States	44 100%

Outcome Measures

1. Primary Outcome

Title	Sensitivity of OTL38 in Detecting Folate Receptor-alpha Positive Ovarian Cancer During Surgery.
Description	Sensitivity for the detection of folate receptor-alpha positive (FRAP) ovarian cancer lesions is defined as the ratio (multiplied by 100) of the number of FRAO ovarian cancer lesions confirmed by both fluorescent light and the pathology/ and immunohistochemistry lab (TP) over the number of FRAP ovarian cancer lesions confirmed by the pathology/ and immunohistochemistry lab (TP+FN). 95% lower one-sided confidence interval was used.
Time Frame	Day of Surgery (Day 1)

Outcome Measure Data

Analysis Population Description

Population includes all patients who received OTL38, underwent cytoreductive surgery for sensitivity analysis, were exposed to fluorescent light using the imaging system, and had at least one FRAP target ovarian cancer lesion. Patients enrolled to the study after adequate number of lesions have been excised and submitted for pathology, and immunohistochemistry evaluation for determining sensitivity, enrolled after protocol amendment 4, were not included in the analysis population.

Arm/Group Title	Experimental
Arm/Group Description	Patient injected with a dose of 0.025 mg/kg OTL38 and undergoes intraoperative imaging
Measure Participants	29
Measure lesions	225
Number (95% Confidence Interval) [percentage of lesions]	97.97

2. Primary Outcome

Title	Positive Predictive Value (PPV) of OTL38 in Detecting Folate Receptor-alpha Positive Ovarian Cancer During Surgery.
Description	PPV for the detection of FRAP ovarian cancer lesions is defined as the ratio (multiplied by 100) of the number of FRAP ovarian cancer lesions confirmed by both fluorescent light and the pathology/ and immunohistochemistry lab (TP) over the number of FRAP ovarian cancer lesions confirmed by fluorescent light (TP + FP). 95% lower one-sided confidence interval was used.
Time Frame	Day of Surgery (Day 1)

Outcome Measure Data

Analysis Population Description

Population includes all patients who received OTL38, underwent cytoreductive surgery for PPV analysis, were exposed to fluorescent light using the imaging system, and had at least one FRAP target ovarian cancer lesion. Patients enrolled to the study after adequate number of lesions have been excised and submitted for pathology, and immunohistochemistry evaluation for determining PPV, enrolled after protocol amendment 4, were not included in the analysis population.

Arm/Group Title	Experimental
Arm/Group Description	Patient injected with a dose of 0.025 mg/kg OTL38 and undergoes intraoperative imaging
Measure Participants	29
Measure lesions	225
Number (95% Confidence Interval) [percentage of lesions]	94.93

Adverse Events

Time Frame	Adverse events were collected from the time of study drug administration throughout the course of the study, ending with Visit 4. The total collection period for each subject was approximately one month.
Adverse Event Reporting Description	The definition of AEs and SAEs for this study was consistent with the clinicaltrials.gov definitions.
Arm/Group Title	Patients Receiving OTL38
Arm/Group Description	All patients in this arm will receive OTL38 for injection and undergo intraoperative imaging. OTL38 Near infrared camera imaging system: Near infrared camera imaging system Laparotomy: primary surgical cytoreduction, interval debulking, or recurrent ovarian cancer surgery
All Cause Mortality
	Patients Receiving OTL38
	Affected / at Risk (%)	# Events
Total	0/44 (0%)
Serious Adverse Events
	Patients Receiving OTL38
	Affected / at Risk (%)	# Events
Total	13/44 (29.5%)
Blood and lymphatic system disorders
Anaemia	1/44 (2.3%)	1
Gastrointestinal disorders
Constipation	1/44 (2.3%)	1
Nausea	1/44 (2.3%)	1
Small intestinal obstruction	1/44 (2.3%)	1
Vomiting	1/44 (2.3%)	1
General disorders
Pyrexia	1/44 (2.3%)	1
Infections and infestations
Postoperative wound infection	2/44 (4.5%)	2
Sepsis	2/44 (4.5%)	2
Clostridium difficile infection	1/44 (2.3%)	1
Haematoma infection	1/44 (2.3%)	1
Pneumonia	1/44 (2.3%)	1
Septic Shock	1/44 (2.3%)	1
Wound abscess	1/44 (2.3%)	1
Renal and urinary disorders
Acute kidney injury	1/44 (2.3%)	1
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/44 (2.3%)	1
Hypoxia	1/44 (2.3%)	1
Plueral effusion	1/44 (2.3%)	1
Vascular disorders
Deep vein thrombosis	1/44 (2.3%)	1
Haematoma	1/44 (2.3%)	1
Haemorrhage	1/44 (2.3%)	1
Other (Not Including Serious) Adverse Events
	Patients Receiving OTL38
	Affected / at Risk (%)	# Events
Total	44/44 (100%)
Blood and lymphatic system disorders
Anaemia	11/44 (25%)	15
Haemorrhagic anaemia	2/44 (4.5%)	2
Leukocytosis	2/44 (4.5%)	2
Thrombocytosis	1/44 (2.3%)	1
Cardiac disorders
Sinus tachycardia	5/44 (11.4%)	5
Tachycardia	1/44 (2.3%)	1
Eye disorders
Lacrimation increased	1/44 (2.3%)	1
Gastrointestinal disorders
Nausea	12/44 (27.3%)	14
Vomiting	14/44 (31.8%)	14
Abdominal distension	4/44 (9.1%)	5
Constipation	4/44 (9.1%)	5
Diarrhoea	4/44 (9.1%)	4
Dysphagia	3/44 (6.8%)	3
Ileus	3/44 (6.8%)	3
Abdominal Pain	2/44 (4.5%)	2
Ascites	2/44 (4.5%)	2
Gastrooesophageal reflux disease	1/44 (2.3%)	1
Ileus paralytic	1/44 (2.3%)	1
Small intestinal obstruction	1/44 (2.3%)	1
General disorders
Pyrexia	5/44 (11.4%)	5
Fatigue	2/44 (4.5%)	2
Chills	1/44 (2.3%)	1
Malaise	1/44 (2.3%)	1
Oedema peripheral	1/44 (2.3%)	1
Infections and infestations
Urinary tract infection	3/44 (6.8%)	3
Pneumonia	2/44 (4.5%)	2
Postoperative wound infection	2/44 (4.5%)	2
Sepsis	2/44 (4.5%)	2
Bronchitis	1/44 (2.3%)	1
Cellulitis	1/44 (2.3%)	1
Clostridium difficile infection	1/44 (2.3%)	1
Device related infection	1/44 (2.3%)	1
Haematoma infection	1/44 (2.3%)	1
Incision site cellulitis	1/44 (2.3%)	1
Klebsiella infection	1/44 (2.3%)	1
Lip infection	1/44 (2.3%)	1
Septic shock	1/44 (2.3%)	1
Vulvovaginal candidiasis	1/44 (2.3%)	1
Wound abcess	1/44 (2.3%)	1
Injury, poisoning and procedural complications
Procedural pain	40/44 (90.9%)	40
Infusion related reaction	5/44 (11.4%)	6
Procedural nausea	3/44 (6.8%)	3
Bladder injury	1/44 (2.3%)	1
Gastrointestinal anastomotic leak	1/44 (2.3%)	1
Wound dehiscence	1/44 (2.3%)	1
Investigations
Electrocardiogram QT prolonged	2/44 (4.5%)	3
Platelet count decreased	2/44 (4.5%)	2
Blood alkaline phosphatase increased	1/44 (2.3%)	1
Urine output decreased	1/44 (2.3%)	1
Metabolism and nutrition disorders
Hypokalaemia	7/44 (15.9%)	7
Hyperglycaemia	3/44 (6.8%)	3
Hyperkalaemia	3/44 (6.8%)	3
Fluid overload	2/44 (4.5%)	2
Hypoalbuminaemia	1/44 (2.3%)	1
Hypocalcaemia	1/44 (2.3%)	1
Hyponatraemia	1/44 (2.3%)	1
Hypophosphataemia	1/44 (2.3%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/44 (2.3%)	1
Nervous system disorders
Headache	1/44 (2.3%)	1
Paraesthesia	1/44 (2.3%)	1
Presyncope	1/44 (2.3%)	1
Seizure	1/44 (2.3%)	1
Psychiatric disorders
Anxiety	2/44 (4.5%)	2
Confusional state	1/44 (2.3%)	1
Delirium	1/44 (2.3%)	1
Hallucination	1/44 (2.3%)	1
Insomnia	1/44 (2.3%)	1
Renal and urinary disorders
Acute kidney injury	1/44 (2.3%)	1
Bladder spasm	1/44 (2.3%)	1
Haematuria	1/44 (2.3%)	1
Pollakiuria	1/44 (2.3%)	1
Urinary retention	1/44 (2.3%)	1
Respiratory, thoracic and mediastinal disorders
Pleural effusion	3/44 (6.8%)	4
Pulmonary oedema	2/44 (4.5%)	2
Atelectasis	1/44 (2.3%)	1
Dyspnoea	1/44 (2.3%)	1
Hypoxia	1/44 (2.3%)	1
Pneumothorax	1/44 (2.3%)	1
Sneezing	1/44 (2.3%)	1
Skin and subcutaneous tissue disorders
Pruritus	2/44 (4.5%)	2
Pruritus generalised	1/44 (2.3%)	1
Skin irritation	1/44 (2.3%)	1
Urticaria	1/44 (2.3%)	1
Vascular disorders
Hypotension	3/44 (6.8%)	3
Deep vein thrombosis	2/44 (4.5%)	2
Haematoma	1/44 (2.3%)	1
Haemorrhage	1/44 (2.3%)	1

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.