Phase 2a Study to Evaluate Suppression of Methotrexate-induced Mucositis by TK112690

• Sponsor: Tosk, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04046250
• Collaborator: Crystal Life Sciences (Other)
• Enrollment: 22
• Locations: 3
• Arms: 2
• Actual Duration (Months): 10.5
• Patients Per Site: 7.3
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

Patients will receive methotrexate at a dose of 45 mg/m2 administered weekly for 4 consecutive weeks as an iv infusion along with a nutritional supplement administered two hours before the methotrexate. One hour before the methotrexate treatment the patients will be administered the first infusion of the day of either TK112690 or placebo depending on randomization. Five hours after the methotrexate treatment the patients will be administered the second treatment of either TK112690 or placebo depending on randomization. The TK112690 dose will be 45 mg/kg.

Condition or Disease	Intervention/Treatment	Phase
Mucositis	Drug: TK-112690; Drug: Placebo TK-112690	Phase 2

Detailed Description

Patients will receive methotrexate at a dose of 45 mg/m2 administered weekly for 4 consecutive weeks as an iv infusion along with a nutritional supplement administered two hours before the methotrexate. One hour before the methotrexate treatment the patients will be administered the first infusion of the day of either TK112690 or placebo depending on randomization infusion. Five hours after the methotrexate treatment the patients will be administered the second treatment of either TK112690 or placebo depending on randomization. The TK112690 dose will be 45 mg/kg.

• A total of 22 patients will be enrolled into one of 2 different dose groups: TK-112690 treated or placebo treated.

• Screening must be within 15 days of subject enrollment.

• Patients will remain for observation at the clinical site for a minimum of 25 hours post initial TK112690 or placebo dose.

• Study follow-up will occur on Week 6, two weeks after the last dosing of methotrexate.

• Blinding: The study will be partially blinded. The patient and investigator will be blinded as to whether TK112690 or placebo is administered. The CRO, sponsor, and site pharmacist will know whether the patient was administered active drug or placebo.

Study Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: A total of 22 patients will be enrolled into one of 2 different: TK112690 treated or placebo treated.A total of 22 patients will be enrolled into one of 2 different: TK112690 treated or placebo treated.
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: The study will be partially blinded. The patient and investigator will be blinded as to whether TK112690 or placebo is administered. The clinical research organization, sponsor, and site pharmacist will know whether the patient was administered active drug or placebo.
• Primary Purpose: Prevention
• Official Title: Phase 2a, Multi-center, Placebo-controlled, Randomized, Partially Blinded, Study Infused TK112690 or or Placebo Administered Along With Methotrexate Weekly for Four Consecutive Weeks to Patients With Recurrent or Residual SCCHN
• Actual Study Start Date: May 15, 2019
• Actual Primary Completion Date: Oct 10, 2019
• Actual Study Completion Date: Mar 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TK112690 TK112690 treatment	Drug: TK-112690; TK112690 treatment pre-methotrexate treatment; Other Names: Treatment
Placebo Comparator: Placebo TK112690 formulation	Drug: Placebo TK-112690; Placebo

Outcome Measures

Primary Outcome Measures

1. Mucositis [up to 4 Weeks]

   Mucositis Evaluation Using Established Scoring Systems: NCI/CTCAE at 4 WKs (Primary) and WHO at 4 WKs (Primary). NCI/CTCAE=National Cancer Institute/Common Terminology Criteria for Adverse Events and WHO=World Health Organization NCI Grades- 0= No mucositis, 1=Mild mucositis (Painless ulcers, erythema, or mild soreness in the absence of lesions), 2=Moderate mucositis (Painful erythema, edema, or ulcers but eating or swallowing possible), 3= Severe mucositis (Painful erythema, edema, or ulcers requiring IV hydration), 4=Life threatening, 5=Death WHO Grades- 0=No mucositis, 1= Mild (Oral soreness, erythema), 2=Moderate (Oral erythema, ulcers, solid diet tolerated), 3=Severe (Oral ulcers, liquid diet only), 4=Life-threatening (Oral alimentation impossible). For both the scales above, a higher score implies greater mucositis. Scale specific mean values for patients in each group (placebo or treated) are calculated and compared by Student's t-test.

Secondary Outcome Measures

1. Incidence Adverse Events That Are Related to Treatment [Measured Weekly Over 4 Weeks of Study]

   Tolerance

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

• Male and female subjects over 18 years old with a histologically or cytological confirmed diagnosis of locally residual, recurrent or metastatic SCCHN.

• Subject must have failed at least one courses of non-MTX chemotherapy, or one course of non-MTX chemotherapy and chemo radiation for treating their SCCHN.

• No prior systemic treatments for cancer (chemotherapy and/or radiotherapy) 4 weeks prior to screening.

• No other concurrent, active, invasive malignancies.

• An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

• Must have a life expectancy of at least 6 months.

• History of brain metastases allowed if disease has stabilized or improved after radiation and/or craniotomy.

• No active angina or uncontrolled arrhythmia.

• No detectable infection including hepatitis B/C and HIV.

• Not pregnant or nursing. Women of childbearing potential must have a negative urine pregnancy test at screening and on the day before dosing and must use medically acceptable methods of birth control. Acceptable methods of birth control include oral or transdermal contraceptives, condoms, spermicidal foam, IUD, progestin implant or injection, abstinence, vaginal ring, or sterilization of partner. The reason for non-childbearing potential, such as bilateral tubal ligation, bilateral oophorectomy, hysterectomy, or post-menopausal for ≥ 1 year, must be specified in the patient's medical history file and CRF.

• Must have adequate organ and immune function as indicated by the following laboratory values:

Parameter Laboratory Values Serum creatinine ≤1.5 x ULN Est. creatinine clearance ≥45 mL/min Total bilirubin ≤2.0 mg/dL (≤34.2 μmol/L) AST & ALT ≤3 x ULN Absolute granulocytes ≥1.5 x 109 cells/L Platelets ≥100,000/µL

● Be able to read and understand, and provide a signature or thumb impression on the Informed Consent Form (ICF) before entering the study.

Exclusion Criteria:

• Subject has not failed at least one courses of non-MTX chemotherapy or one course of non-MTX chemotherapy and chemo radiation for treating their SCCHN.

• Uncontrolled active infection.

• Current mucositis (>Grade 1).

• Pregnant or nursing mother.

• Prior history of a cerebrovascular accident or hemorrhage.

• Congestive heart failure, as defined by New York Heart Association class III or IV.

• Uncontrolled hypertension.

• Active psychiatric/mental illness making informed consent or useful clinical follow-up unlikely.

• Subjects who have previously been enrolled into this study and subsequently withdrew.

• Subject receiving other investigational agent(s).

• Any systemic immunosuppressive medication/therapy (eg, other chemotherapy, steroids).

• Any significant systemic illness, unstable or severe medical condition(s) that could put the subject at risk during the study, interfere with outcome measures, or affect compliance with the protocol procedures such as intercurrent infection and/or autoimmune disease, ie, any condition that compromises the immune system.

• Known or suspected intolerance or hypersensitivity to the study materials (TK-112690 and/or excipients or closely related compounds).

• Subjects, who have received, or plan to receive, radiation or chemotherapy within 4 weeks of screening.

• Subjects that have a history of poor compliance in clinical research studies.

• Subjects that have participated in any other investigative clinical trial in the past 4 weeks.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Bangalore Cancer	Bangalore	Karnataka	India	560091
2	Karnatak Cancer Therapy and Research Institute	Navanagar	Karnataka	India	580025
3	Netaji Subhash Chandra Bose Cancer Hospital	Kolkata	West Bengal	India	700094

Sponsors and Collaborators

• Tosk, Inc.
• Crystal Life Sciences

Investigators

• Study Director: William Garland, Tosk, Inc.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 25, 2019

More Information

Publications

None provided.

• Responsible Party: Tosk, Inc.
• ClinicalTrials.gov Identifier: NCT04046250
• Other Study ID Numbers: CLP-2690-0003
• First Posted: Aug 6, 2019
• Last Update Posted: Jun 3, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Tosk, Inc.: Mucositis; Methotrexate; Uridine Phosphorylase Inhibitor; Head and Neck Cancer
• Additional relevant MeSH terms: Mucositis

Study Results

Participant Flow

Arm/Group Title	TK112690	Placebo
Arm/Group Description	TK112690 treatment TK-112690: TK112690 treatment pre-methotrexate treatment	TK112690 formulation Placebo TK-112690: Placebo
Period Title: Overall Study
STARTED	11	11
COMPLETED	8	7
NOT COMPLETED	3	4

Baseline Characteristics

Arm/Group Title	TK112690	Placebo	Total
Arm/Group Description	TK112690 treatment TK-112690: TK112690 treatment pre-methotrexate treatment	TK112690 formulation Placebo TK-112690: Placebo	Total of all reporting groups
Overall Participants	11	11	22
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54 (11)	49 (13)	52 (12)
Sex: Female, Male (Count of Participants)
Female	7 63.6%	8 72.7%	15 68.2%
Male	4 36.4%	3 27.3%	7 31.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	11 100%	11 100%	22 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
India	11 100%	11 100%	22 100%

Outcome Measures

1. Primary Outcome

Title	Mucositis
Description	Mucositis Evaluation Using Established Scoring Systems: NCI/CTCAE at 4 WKs (Primary) and WHO at 4 WKs (Primary). NCI/CTCAE=National Cancer Institute/Common Terminology Criteria for Adverse Events and WHO=World Health Organization NCI Grades- 0= No mucositis, 1=Mild mucositis (Painless ulcers, erythema, or mild soreness in the absence of lesions), 2=Moderate mucositis (Painful erythema, edema, or ulcers but eating or swallowing possible), 3= Severe mucositis (Painful erythema, edema, or ulcers requiring IV hydration), 4=Life threatening, 5=Death WHO Grades- 0=No mucositis, 1= Mild (Oral soreness, erythema), 2=Moderate (Oral erythema, ulcers, solid diet tolerated), 3=Severe (Oral ulcers, liquid diet only), 4=Life-threatening (Oral alimentation impossible). For both the scales above, a higher score implies greater mucositis. Scale specific mean values for patients in each group (placebo or treated) are calculated and compared by Student's t-test.
Time Frame	up to 4 Weeks

Outcome Measure Data

Analysis Population Description

Patients with SCCHN who have failed at least one prior treatment of chemotherapy and/or radiation

Arm/Group Title	TK112690	Placebo
Arm/Group Description	TK112690 treatment TK-112690: TK112690 treatment pre-methotrexate treatment	TK112690 formulation Placebo TK-112690: Placebo
Measure Participants	11	11
NCI/CTCAE at 4 WKs	0.37 (0.19)	2.84 (0.29)
WHO at 4 WKs	0.34 (0.17)	2.87 (0.31)

2. Secondary Outcome

Title	Incidence Adverse Events That Are Related to Treatment
Description	Tolerance
Time Frame	Measured Weekly Over 4 Weeks of Study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TK112690	Placebo
Arm/Group Description	TK112690 treatment TK-112690: TK112690 treatment pre-methotrexate treatment	TK112690 formulation Placebo TK-112690: Placebo
Measure Participants	11	11
SAEs	0 0%	2 18.2%
Deaths	0 0%	1 9.1%
TEAE GI and Related	1 9.1%	11 100%

Adverse Events

Time Frame	6 Weeks
Arm/Group Title	TK112690		Placebo
Arm/Group Description	TK112690 treatment TK-112690: TK112690 treatment pre-methotrexate treatment		TK112690 formulation Placebo TK-112690: Placebo
All Cause Mortality
	TK112690		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		1/11 (9.1%)
Serious Adverse Events
	TK112690		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		2/11 (18.2%)
Blood and lymphatic system disorders
Neutropenia	0/11 (0%)	0	2/11 (18.2%)	2
Other (Not Including Serious) Adverse Events
	TK112690		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/11 (9.1%)		7/11 (63.6%)
Gastrointestinal disorders
GI Disorders	1/11 (9.1%)		7/11 (63.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Each of the three clinical sites has a PI. Each PI is bound by a CDA covering the clinical data. Tosk intends to prepare a manuscript reporting results from this trial combined with the results from the Phase 1b clinical trial. All the PIs will have a chance to review and approve the findings reported in the manuscript. Tosk expects to submit the manuscript for publication in early 2022.