A Phase 2 Study of Lamivudine in Patients With p53 Mutant Metastatic Colorectal Cancer

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03144804
• Collaborator: (none)
• Enrollment: 36
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 85
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This research study is studying a drug as a possible treatment for p53 mutant metastatic colorectal cancer.

The drug involved in this study is:

-Lamivudine

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer Metastatic	Drug: Lamivudine	Phase 2

Detailed Description

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved lamivudine for this specific disease but it has been approved for other uses.

In this research study, the investigators are studying the effects of lamivudine on this type of cancer. This drug may help prevent the growth and spread of the cancer cells to other parts of the body. The investigators have discovered that this particular type of colon cancer, which has a p53 mutation may be sensitive to treatment with lamivudine by impairing the ability of the cancer cells to grow.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of Lamivudine in Patients With p53 Mutant Metastatic Colorectal Cancer
• Actual Study Start Date: Oct 31, 2017
• Actual Primary Completion Date: Mar 26, 2020
• Anticipated Study Completion Date: Nov 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lamivudine Lamivudine administered orally every 4 weeks Treatment cycles will last 28 consecutive days The dosage will be determine by the PI	Drug: Lamivudine; This drug may help prevent the growth and spread of the cancer cells to other parts of the body.; Other Names: Combivir

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate [2 years]

   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT scan or MRI, complete response (CR) is the disappearance of all target lesions and partial response (PR) is a >/=30% decrease in the sum of the longest diameter of target lesions. Overall Response (OR) = CR + PR. The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.

Secondary Outcome Measures

1. Progression Free Survival [2 years]

   Progression-Free Survival (PFS) is defined as the time from registration to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation.

2. Overall Survival [2 years]

   Overall Survival (OS) is defined as the time from registration to death due to any cause, or censored at date last known alive.

3. Overall Disease Control Rate [2 years]

   Disease control rate (DCR) is a composite of overall response rate (ORR) and stable disease and is useful to measure the efficacy of therapies that have tumoristatic effects rather than tumoricidal effects.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must have histologically confirmed adenocarcinoma of the colon that has metastasized (stage 4) and is TP53 mutant/deleted by a CLIA approved genetic test. Only known loss of function TP53 mutation/deletion will be eligible for this study.

• Participants must have measureable disease, defined as at least on lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as > 20mm with conventional techniques or > 10 mm with spiral CT scan, MRI or calipers by clinical exam. See section 11 for evaluation of measurable disease

• Patients must be resistant to or intolerant of 5FU, oxaliplatin, irinotecan, bevacizumab and cetuximab/panitumumab (if RAS wild type)

• Age 18 or older.

• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

• Life expectancy of greater than 8 weeks.

• Participants must have normal organ and marrow function as defined below:

• absolute neutrophil count ≥1,200/mcL

• platelets ≥75,000/mcL

• total bilirubin ≤1.5 × institutional upper limit of normal within normal

• AST(SGOT)/ALT(SGPT) ≤5 × institutional upper limit of normal

• creatinine within normal institutional limits OR

• creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.

• The effects of lamivudine on the developing human fetus are known to be teratogenic. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of lamivudine administration.

• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosourea or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.

• Participants who are receiving any other investigational agents.

• Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to lamivudine.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• Pregnant women are excluded from this study because lamivudine is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with lamivudine, breastfeeding should be discontinued if the mother is treated with lamivudine.

• HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with lamivudine

• HBV positive participants will be excluded given the known effects of lamivudine on HBV.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts general Hospital	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

• Massachusetts General Hospital

Investigators

• Principal Investigator: Aparna R. Parikh, MD, Massachusetts General Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 14, 2019
• Informed Consent Form - Aug 23, 2019

More Information

Publications

None provided.

• Responsible Party: Aparna Parikh, Principal Investigator, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT03144804
• Other Study ID Numbers: 17-044
• First Posted: May 9, 2017
• Last Update Posted: Aug 26, 2021
• Last Verified: Aug 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 Aparna Parikh, Principal Investigator, Massachusetts General Hospital: Colorectal Cancer
• Additional relevant MeSH terms: Colorectal Neoplasms; Lamivudine

Study Results

Participant Flow

Arm/Group Title	Lamivudine
Arm/Group Description	Lamivudine administered orally every 4 weeks Treatment cycles will last 28 consecutive days The dosage will be determine by the PI Lamivudine: This drug may help prevent the growth and spread of the cancer cells to other parts of the body.
Period Title: Overall Study
STARTED	36
COMPLETED	32
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Lamivudine
Arm/Group Description	Lamivudine administered orally every 4 weeks Treatment cycles will last 28 consecutive days The dosage will be determine by the PI Lamivudine: This drug may help prevent the growth and spread of the cancer cells to other parts of the body.
Overall Participants	32
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	24 75%
>=65 years	8 25%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59
Sex: Female, Male (Count of Participants)
Female	14 43.8%
Male	18 56.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 6.3%
Not Hispanic or Latino	29 90.6%
Unknown or Not Reported	1 3.1%
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	0 0%
White	29 90.6%
More than one race	1 3.1%
Unknown or Not Reported	2 6.3%
Region of Enrollment (participants) [Number]
United States	32 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT scan or MRI, complete response (CR) is the disappearance of all target lesions and partial response (PR) is a >/=30% decrease in the sum of the longest diameter of target lesions. Overall Response (OR) = CR + PR. The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lamivudine
Arm/Group Description	Lamivudine administered orally every 4 weeks Treatment cycles will last 28 consecutive days The dosage will be determine by the PI Lamivudine: This drug may help prevent the growth and spread of the cancer cells to other parts of the body.
Measure Participants	32
Number [participants]	0 0%

2. Secondary Outcome

Title	Progression Free Survival
Description	Progression-Free Survival (PFS) is defined as the time from registration to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Of the 32 analyzed participants, 5 participants were censored in PFS analysis because they were taken off treatment before their first radiographic progression.

Arm/Group Title	Lamivudine
Arm/Group Description	Lamivudine administered orally every 4 weeks Treatment cycles will last 28 consecutive days The dosage will be determine by the PI Lamivudine: This drug may help prevent the growth and spread of the cancer cells to other parts of the body.
Measure Participants	27
Median (95% Confidence Interval) [days]	56

3. Secondary Outcome

Title	Overall Survival
Description	Overall Survival (OS) is defined as the time from registration to death due to any cause, or censored at date last known alive.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Overall Disease Control Rate
Description	Disease control rate (DCR) is a composite of overall response rate (ORR) and stable disease and is useful to measure the efficacy of therapies that have tumoristatic effects rather than tumoricidal effects.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Adverse event data was collected from the start of protocol therapy up until participants were taken off study, a median of approximately 7 months.
Adverse Event Reporting Description	Adverse events were evaluated through regular investigator assessment and regular laboratory testing.
Arm/Group Title	Lamivudine
Arm/Group Description	Lamivudine administered orally every 4 weeks Treatment cycles will last 28 consecutive days The dosage will be determine by the PI Lamivudine: This drug may help prevent the growth and spread of the cancer cells to other parts of the body.
All Cause Mortality
	Lamivudine
	Affected / at Risk (%)	# Events
Total	1/32 (3.1%)
Serious Adverse Events
	Lamivudine
	Affected / at Risk (%)	# Events
Total	9/32 (28.1%)
Blood and lymphatic system disorders
Leukocytosis	1/32 (3.1%)	1
Cardiac disorders
Atrial fibrillation	1/32 (3.1%)	1
Gastrointestinal disorders
Abdominal pain	2/32 (6.3%)	5
Small intestinal obstruction	3/32 (9.4%)	3
Diarrhea	1/32 (3.1%)	1
Vomiting	1/32 (3.1%)	1
Nausea	1/32 (3.1%)	1
General disorders
Death NOS	1/32 (3.1%)	1
Vaginal bleeding	1/32 (3.1%)	1
Fever	1/32 (3.1%)	1
Chest pain	1/32 (3.1%)	1
Fatigue	1/32 (3.1%)	1
Osteomyelitis	1/32 (3.1%)	1
Metabolism and nutrition disorders
Dehydration	1/32 (3.1%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	4/32 (12.5%)	5
Other (Not Including Serious) Adverse Events
	Lamivudine
	Affected / at Risk (%)	# Events
Total	31/32 (96.9%)
Blood and lymphatic system disorders
Anemia	19/32 (59.4%)	50
Cardiac disorders
Atrial fibrillation	2/32 (6.3%)	2
Palpitations	2/32 (6.3%)	2
Ventricular tachycardia	1/32 (3.1%)	1
Ear and labyrinth disorders
Vertigo	2/32 (6.3%)	2
Gastrointestinal disorders
Abdominal distension	2/32 (6.3%)	2
Abdominal pain	14/32 (43.8%)	19
Anal hemorrhage	1/32 (3.1%)	1
Bloating	1/32 (3.1%)	1
Constipation	10/32 (31.3%)	11
Diarrhea	8/32 (25%)	10
Dry mouth	2/32 (6.3%)	2
Dyspepsia	1/32 (3.1%)	1
Gastroesophageal reflux disease	2/32 (6.3%)	2
Gastrointestinal disorders - Other	1/32 (3.1%)	1
Gastrointestinal disorders - Other	1/32 (3.1%)	1
Gastrointestinal disorders - Other	1/32 (3.1%)	1
Gastrointestinal pain	1/32 (3.1%)	1
Small intestinal obstruction	3/32 (9.4%)	4
Nausea	15/32 (46.9%)	19
Rectal fistula	1/32 (3.1%)	1
Rectal hemorrhage	1/32 (3.1%)	1
Vomiting	8/32 (25%)	10
General disorders
Chills	3/32 (9.4%)	5
Edema face	1/32 (3.1%)	1
Edema limbs	2/32 (6.3%)	3
Fatigue	20/32 (62.5%)	22
Fever	6/32 (18.8%)	6
Gait disturbance	1/32 (3.1%)	1
Hypothermia	1/32 (3.1%)	1
Irritability	1/32 (3.1%)	1
Malaise	2/32 (6.3%)	2
Non-cardiac chest pain	1/32 (3.1%)	1
Pain	15/32 (46.9%)	18
General disorders and administration site conditions - Other	1/32 (3.1%)	1
General disorders and administration site conditions - Other	1/32 (3.1%)	1
General disorders and administration site conditions - Other	1/32 (3.1%)	1
General disorders and administration site conditions - Other	1/32 (3.1%)	1
General disorders and administration site conditions - Other	1/32 (3.1%)	1
General disorders and administration site conditions - Other	1/32 (3.1%)	1
General disorders and administration site conditions - Other	1/32 (3.1%)	1
General disorders and administration site conditions - Other	1/32 (3.1%)	1
General disorders and administration site conditions - Other	1/32 (3.1%)	1
General disorders and administration site conditions - Other	1/32 (3.1%)	1
General disorders and administration site conditions - Other	1/32 (3.1%)	1
General disorders and administration site conditions - Other	1/32 (3.1%)	1
General disorders and administration site conditions - Other	1/32 (3.1%)	1
General disorders and administration site conditions - Other	1/32 (3.1%)	1
General disorders and administration site conditions - Other	1/32 (3.1%)	1
General disorders and administration site conditions - Other	1/32 (3.1%)	1
General disorders and administration site conditions - Other	1/32 (3.1%)	1
Hepatobiliary disorders
Portal vein thrombosis	1/32 (3.1%)	1
Infections and infestations
Lip infection	1/32 (3.1%)	1
Lung infection	1/32 (3.1%)	1
Sinusitis	1/32 (3.1%)	1
Skin infection	1/32 (3.1%)	1
Urinary tract infection	1/32 (3.1%)	1
Injury, poisoning and procedural complications
Bruising	2/32 (6.3%)	2
Wound complication	1/32 (3.1%)	1
Wound dehiscence	1/32 (3.1%)	1
Investigations
Alanine aminotransferase increased	5/32 (15.6%)	10
Alkaline phosphatase increased	17/32 (53.1%)	24
Aspartate aminotransferase increased	13/32 (40.6%)	20
Blood bilirubin increased	7/32 (21.9%)	11
Creatinine increased	3/32 (9.4%)	5
Investigations - Other	1/32 (3.1%)	1
Lymphocyte count decreased	18/32 (56.3%)	54
Neutrophil count decreased	2/32 (6.3%)	2
Platelet count decreased	5/32 (15.6%)	9
Weight loss	2/32 (6.3%)	3
White blood cell decreased	7/32 (21.9%)	13
Metabolism and nutrition disorders
Anorexia	9/32 (28.1%)	11
Dehydration	2/32 (6.3%)	3
Hyperglycemia	17/32 (53.1%)	53
Hyperkalemia	1/32 (3.1%)	1
Hypermagnesemia	1/32 (3.1%)	1
Hypernatremia	2/32 (6.3%)	2
Hypoalbuminemia	5/32 (15.6%)	7
Hypoalbuminemia	1/32 (3.1%)	1
Hypocalcemia	5/32 (15.6%)	11
Hypokalemia	1/32 (3.1%)	2
Hypomagnesemia	4/32 (12.5%)	4
Hyponatremia	14/32 (43.8%)	23
Hypophosphatemia	8/32 (25%)	9
Musculoskeletal and connective tissue disorders
Back pain	6/32 (18.8%)	6
Flank pain	1/32 (3.1%)	1
Generalized muscle weakness	3/32 (9.4%)	4
Myalgia	2/32 (6.3%)	2
Pain in extremity	5/32 (15.6%)	6
Nervous system disorders
Dizziness	4/32 (12.5%)	4
Dysgeusia	2/32 (6.3%)	2
Dysphasia	1/32 (3.1%)	1
Headache	4/32 (12.5%)	4
Paresthesia	1/32 (3.1%)	1
Peripheral sensory neuropathy	3/32 (9.4%)	3
Psychiatric disorders
Anxiety	4/32 (12.5%)	4
Confusion	1/32 (3.1%)	1
Depression	1/32 (3.1%)	1
Insomnia	3/32 (9.4%)	3
Renal and urinary disorders
Proteinuria	2/32 (6.3%)	4
Urine discoloration	1/32 (3.1%)	1
Reproductive system and breast disorders
Perineal pain	1/32 (3.1%)	1
Scrotal pain	1/32 (3.1%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/32 (3.1%)	1
Cough	7/32 (21.9%)	9
Dyspnea	9/32 (28.1%)	10
Postnasal drip	1/32 (3.1%)	1
Skin and subcutaneous tissue disorders
Dry skin	1/32 (3.1%)	1
Erythema multiforme	1/32 (3.1%)	1
Rash maculo-papular	3/32 (9.4%)	4
Skin/subcutaneous tissue disorders - Other	1/32 (3.1%)	1
Skin/subcutaneous tissue disorders - Other	1/32 (3.1%)	1
Pruritus	1/32 (3.1%)	1
Vascular disorders
Hypertension	4/32 (12.5%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.