PhII Trial Panitumumab, Nivolumab, Ipilimumab in Kras/Nras/BRAF Wild-type MSS Refractory mCRC

• Sponsor: UNC Lineberger Comprehensive Cancer Center (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03442569
• Collaborator: Amgen (Industry), Bristol-Myers Squibb (Industry)
• Enrollment: 56
• Locations: 5
• Arm: 1
• Anticipated Duration (Months): 72.7
• Patients Per Site: 11.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

To investigate the combination of nivolumab and ipilimumab with panitumumab in subjects with unresectable, refractory, KRAS/NRAS/BRAF wild-type, microsatellite stable (MSS) metastatic colorectal cancer.

Condition or Disease	Intervention/Treatment	Phase
Colon Cancer	Drug: Panitumumab; Drug: Nivolumab; Drug: Ipilimumab	Phase 2

Detailed Description

The investigators will conduct a single-arm, open-label Phase II clinical trial investigating the combination of nivolumab and ipilimumab with panitumumab in subjects with unresectable, refractory, KRAS/NRAS/BRAF wild-type, microsatellite stable (MSS) metastatic colorectal cancer (mCRC). There will be an initial safety lead-in cohort to ensure the combination is well-tolerated. The primary objective of this study is to estimate the overall response rate in these subjects at 12 weeks . Secondary objectives include the following: estimating the overall response rate in these subjects at 12 weeks by immune-related RECIST criteria (irRECIST), estimating the best response rate by both RECIST 1.1 and irRECIST criteria, estimating progression-free survival (PFS) and duration of response using both RECIST 1.1 and irRECIST criteria, estimating overall survival (OS), and characterizing the safety issues associated with this regimen. Exploratory objectives involve investigating various biomarkers and peripheral blood and tumor assays.

Study Design

• Study Type: Interventional
• Actual Enrollment: 56 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: This will be a single-arm, open-label, multicenter Phase II clinical trial investigating the clinical efficacy of nivolumab, ipilimumab, and panitumumab in subjects with unresectable refractory KRAS/NRAS/BRAF wild-type microsatellite stable metastatic colorectal cancer after an initial safety lead-in cohort to ensure the three drug combination is well-tolerated.This will be a single-arm, open-label, multicenter Phase II clinical trial investigating the clinical efficacy of nivolumab, ipilimumab, and panitumumab in subjects with unresectable refractory KRAS/NRAS/BRAF wild-type microsatellite stable metastatic colorectal cancer after an initial safety lead-in cohort to ensure the three drug combination is well-tolerated.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Multicenter Trial of Panitumumab, Nivolumab, and Ipilimumab for KRAS/NRAS/BRAF Wild-type MSS Refractory Metastatic Colorectal Adenocarcinoma
• Actual Study Start Date: Mar 9, 2018
• Actual Primary Completion Date: Sep 21, 2020
• Anticipated Study Completion Date: Mar 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Open-label, single arm, Phase II Nivolumab and ipilimumab with panitumumab	Drug: Panitumumab; 6 mg/kg via IV every 2 weeks in combination with nivolumab and ipilimumab; Other Names: Vectibix ; Drug: Nivolumab; 240 mg via IV every 2 weeks in combination with panitumumab and ipilimumab; Other Names: Opdivo ; Drug: Ipilimumab; 1 mg/kg via IV every 6 weeks in combination with nivolumab and panitumumab; Other Names: Yervoy

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate [12 weeks]

   Overall Response Rate (ORR) = CR + PR Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions

Secondary Outcome Measures

1. Overall Response Rate Per irRECIST [12 weeks]

   Overall Response Rate (ORR) = irCR + irPR Per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) for target and/or non-target lesions and assessed by imaging: Complete Response (irCR), Disappearance of all lesions, no new lesions, lymph nodes < 10 mm in short axis; Partial Response (irPR), ≥30% decrease in the sum of target lesions and non-target lesions are irNN; Stable response (irSD), not meeting criteria for irCR, irPR, or irPD; Progressive Disease (irPD), ≥20% increase in tumor burden and minimum 5 mm absolute increase in compared to nadir; for no new non-target or (irNN) and where irPR or irPD are confirmed by a repeat, consecutive assessment no less than 4 weeks later

2. Length of Progression Free Survival [Up to 3 years]

   Time from first day of treatment until disease progression as defined by RECIST, irRECIST, or death from any cause

3. Length of Overall Survival [Up to 3 years]

   Time from first day of treatment until death from any cause

4. Duration of Response [Up to 3 years]

   Time from documentation of tumor response to disease progression

5. Toxicity of Treatment [Up to 36 month]

   The number of treatment-emergent grade 3 and 4 toxicities as defined by National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Histologically or cytologically confirmed colorectal adenocarcinoma, with unresectable metastatic or locally advanced disease documented on diagnostic imaging studies.

2. Previously received 1-2 prior lines of therapy. Subjects who relapse within 6 months of adjuvant chemotherapy comprised of oxaliplatin and a fluoropyrimidine will have their adjuvant therapy count as one prior line of therapy.

3. Confirmed wild-type in KRAS and NRAS codons 12, 13, 59, 61, 117, and 146; and BRAF codon 600, by standard of care testing of tumor specimen. Tissue used for testing may have been collected from primary or metastatic site.

4. Microsatellite stable as detected by PCR-based assay or CLIA-certified sequencing methodology such as Foundation One; or mismatch repair proficient as detected by immunohistochemistry showing intact nuclear staining of MLH1, MSH2, MSH6, and PMS2

5. Radiographically measurable disease present per RECIST 1.1

6. Age ≥ 18 years at the time of consent.

7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

8. Blood counts performed within 3 weeks prior to starting study therapy must have absolute neutrophil count ≥ 1,500/mm3, platelets ≥ 100,000/mm3, and hemoglobin ≥ 9 g/dL.

*Note: Hematology and other lab parameters that are ≤ grade 2 but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy.

1. Liver function tests performed within 3 weeks prior to starting study therapy must have total bilirubin ≤ 1.5 x upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase ≤ 3 x ULN, and albumin ≥ 2.5 g/dL.

2. Serum creatinine performed within 3 weeks prior to starting study therapy must be ≤ 1.5 x ULN, or have calculated creatinine clearance (using Cockcroft-Gault formula provided in Appendix 11.3) of ≥ 50 mL/minute.

3. Females of childbearing potential must have a negative serum pregnancy test within 24 hours prior to receiving the first dose of study medication. Females of childbearing potential must agree to use 2 methods of effective contraception or abstain from heterosexual sex throughout the treatment period and for 5 months after the last dose of study treatment. Females of childbearing potential are women who have not been surgically sterilized (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or have not been free of menses for >1 year.

4. Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 7 months after the last dose of study treatment.

5. Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.

6. An adequate amount of archival tumor tissue must be available at baseline to be eligible for enrollment in the study. If archival tissue is not available or is inadequate, then the subject must consent to undergo a mandatory biopsy at baseline in order to participate in the study.

Exclusion Criteria:

1. Past treatment with an antibody targeting EGFR including cetuximab or panitumumab.

2. Past treatment with an antibody targeting immune checkpoints including CTLA-4, PD-1, PD-L1, PD-L2, or CD137.

3. Known untreated brain metastasis or brain metastasis treated within 3 months prior to enrollment in this trial.

4. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.

5. Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease free for at least five years.

6. Treatment within 21 days of the first dose of study drug with any other chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment for the treatment of malignancy, or failure to recover from adverse effects of prior therapies administered over 4 weeks prior to Study Day 1. All toxicities from prior therapies must be ≤ Grade 1 (or ≤ Grade 2 for alopecia or peripheral neuropathy). Prior systemic treatment in the adjuvant setting is allowed. See note above under inclusion 3.1.8

7. Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent, or compliance to the study procedures.

8. Pregnant or breastfeeding, or planning to become pregnant within 6 months after the end of treatment. (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).

9. History of organ allograft or other history of immunodeficiency, or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before the first dose of investigational treatment.

10. Inability or unwillingness to comply with study and/or follow-up requirements.

11. Any major surgery, extensive radiotherapy, chemotherapy with clinically significant delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to randomization and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to randomization.

12. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug.

13. Known Human Immunodeficiency Virus (HIV), Hepatitis B virus (HBV), or Hepatitis C virus (HCV) infection. Subjects with laboratory evidence of cleared HBV and HCV infection will be permitted.

14. Active autoimmune disease requiring systemic treatment in the past 3 months (for example with disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators, local steroid injections, or inhaled or topical steroids would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study.

15. Active infection requiring intravenous systemic therapy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Moffitt Cancer Center	Tampa	Florida	United States	33612
2	Indiana University Health Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
3	University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27509
4	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
5	University of Washington - Seattle Cancer Care Alliance	Seattle	Washington	United States	98109

Sponsors and Collaborators

• UNC Lineberger Comprehensive Cancer Center
• Amgen
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Autumn McRee, MD, University of North Carolina, Chapel Hill

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 1, 2020

More Information

Additional Information:

• University of North Carolina Lineberger Comprehensive Cancer Center

Publications

None provided.

• Responsible Party: UNC Lineberger Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT03442569
• Other Study ID Numbers: LCCC1632
• First Posted: Feb 22, 2018
• Last Update Posted: Nov 11, 2021
• Last Verified: Nov 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Colonic Neoplasms; Nivolumab; Ipilimumab; Panitumumab

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from 5 medical institutions between March 2018 and June 2020.
Pre-assignment Detail	A total of 61 subjects were consented to the trial, but 5 were deemed to be ineligible during screening and therefore were not enrolled on the trial.

Arm/Group Title	Open-label, Single Arm, Phase II
Arm/Group Description	Nivolumab and ipilimumab with panitumumab Panitumumab: 6 mg/kg via IV every 2 weeks in combination with nivolumab and ipilimumab Nivolumab: 240 mg via IV every 2 weeks in combination with panitumumab and ipilimumab Ipilimumab: 1 mg/kg via IV every 6 weeks in combination with nivolumab and panitumumab
Period Title: Overall Study
STARTED	56
Started Treatment	55
COMPLETED	55
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Open-label, Single Arm, Phase II
Arm/Group Description	Nivolumab and ipilimumab with panitumumab Panitumumab: 6 mg/kg via IV every 2 weeks in combination with nivolumab and ipilimumab Nivolumab: 240 mg via IV every 2 weeks in combination with panitumumab and ipilimumab Ipilimumab: 1 mg/kg via IV every 6 weeks in combination with nivolumab and panitumumab
Overall Participants	56
Age, Customized (Count of Participants)
30-39	1 1.8%
40-49	9 16.1%
50-59	25 44.6%
60-69	17 30.4%
70-79	4 7.1%
Sex: Female, Male (Count of Participants)
Female	19 33.9%
Male	37 66.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 1.8%
Not Hispanic or Latino	54 96.4%
Unknown or Not Reported	1 1.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	3 5.4%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	7 12.5%
White	44 78.6%
More than one race	0 0%
Unknown or Not Reported	2 3.6%
Region of Enrollment (participants) [Number]
United States	56 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate
Description	Overall Response Rate (ORR) = CR + PR Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Seven participants were unevaluable for the primary endpoint at 12 weeks

Arm/Group Title	Open-label, Single Arm, Phase II
Arm/Group Description	Nivolumab and ipilimumab with panitumumab Panitumumab: 6 mg/kg via IV every 2 weeks in combination with nivolumab and ipilimumab Nivolumab: 240 mg via IV every 2 weeks in combination with panitumumab and ipilimumab Ipilimumab: 1 mg/kg via IV every 6 weeks in combination with nivolumab and panitumumab
Measure Participants	49
Number (95% Confidence Interval) [percentage of participants]	37 66.1%

2. Secondary Outcome

Title	Overall Response Rate Per irRECIST
Description	Overall Response Rate (ORR) = irCR + irPR Per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) for target and/or non-target lesions and assessed by imaging: Complete Response (irCR), Disappearance of all lesions, no new lesions, lymph nodes < 10 mm in short axis; Partial Response (irPR), ≥30% decrease in the sum of target lesions and non-target lesions are irNN; Stable response (irSD), not meeting criteria for irCR, irPR, or irPD; Progressive Disease (irPD), ≥20% increase in tumor burden and minimum 5 mm absolute increase in compared to nadir; for no new non-target or (irNN) and where irPR or irPD are confirmed by a repeat, consecutive assessment no less than 4 weeks later
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Seven participants were unevaluable for the primary endpoint at 12 weeks

Arm/Group Title	Open-label, Single Arm, Phase II
Arm/Group Description	Nivolumab and ipilimumab with panitumumab Panitumumab: 6 mg/kg via IV every 2 weeks in combination with nivolumab and ipilimumab Nivolumab: 240 mg via IV every 2 weeks in combination with panitumumab and ipilimumab Ipilimumab: 1 mg/kg via IV every 6 weeks in combination with nivolumab and panitumumab
Measure Participants	49
Number (95% Confidence Interval) [percentage of participants]	37 66.1%

3. Secondary Outcome

Title	Length of Progression Free Survival
Description	Time from first day of treatment until disease progression as defined by RECIST, irRECIST, or death from any cause
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Length of Overall Survival
Description	Time from first day of treatment until death from any cause
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Duration of Response
Description	Time from documentation of tumor response to disease progression
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Toxicity of Treatment
Description	The number of treatment-emergent grade 3 and 4 toxicities as defined by National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03)
Time Frame	Up to 36 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	From Day 1 of treatment up to 3 years after completion of treatment
Arm/Group Title	Open-label, Single Arm, Phase II
Arm/Group Description	Nivolumab and ipilimumab with panitumumab Panitumumab: 6 mg/kg via IV every 2 weeks in combination with nivolumab and ipilimumab Nivolumab: 240 mg via IV every 2 weeks in combination with panitumumab and ipilimumab Ipilimumab: 1 mg/kg via IV every 6 weeks in combination with nivolumab and panitumumab
All Cause Mortality
	Open-label, Single Arm, Phase II
	Affected / at Risk (%)	# Events
Total	27/56 (48.2%)
Serious Adverse Events
	Open-label, Single Arm, Phase II
	Affected / at Risk (%)	# Events
Total	21/56 (37.5%)
Blood and lymphatic system disorders
Blood and lymphatic system disorders - Other, specify	1/56 (1.8%)
Hemolysis	1/56 (1.8%)
Cardiac disorders
Chest pain - cardiac	1/56 (1.8%)
Myocarditis	1/56 (1.8%)
Endocrine disorders
Adrenal insufficiency	3/56 (5.4%)
Endocrine disorders - Other, specify	1/56 (1.8%)
Gastrointestinal disorders
Abdominal pain	2/56 (3.6%)
Colonic obstruction	1/56 (1.8%)
Colonic perforation	1/56 (1.8%)
Diarrhea	3/56 (5.4%)
Gastrointestinal disorders - Other, specify	2/56 (3.6%)
Nausea	1/56 (1.8%)
Small intestinal obstruction	1/56 (1.8%)
Vomiting	2/56 (3.6%)
General disorders
Fatigue	2/56 (3.6%)
Flu like symptoms	1/56 (1.8%)
Infections and infestations
Infections and infestations - Other, specify	2/56 (3.6%)
Sepsis	1/56 (1.8%)
Investigations
Alanine aminotransferase increased	1/56 (1.8%)
Alkaline phosphatase increased	1/56 (1.8%)
Aspartate aminotransferase increased	2/56 (3.6%)
Blood bilirubin increased	1/56 (1.8%)
Metabolism and nutrition disorders
Anorexia	1/56 (1.8%)
Dehydration	1/56 (1.8%)
Nervous system disorders
Headache	1/56 (1.8%)
Psychiatric disorders
Delirium	1/56 (1.8%)
Renal and urinary disorders
Acute kidney injury	1/56 (1.8%)
Urinary retention	1/56 (1.8%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/56 (1.8%)
Hypoxia	1/56 (1.8%)
Pneumonitis	1/56 (1.8%)
Skin and subcutaneous tissue disorders
Rash acneiform	1/56 (1.8%)
Rash maculo-papular	1/56 (1.8%)
Stevens-Johnson syndrome	1/56 (1.8%)
Vascular disorders
Hypotension	1/56 (1.8%)
Thromboembolic event	1/56 (1.8%)
Other (Not Including Serious) Adverse Events
	Open-label, Single Arm, Phase II
	Affected / at Risk (%)	# Events
Total	56/56 (100%)
Blood and lymphatic system disorders
Anemia	16/56 (28.6%)
Blood and lymphatic system disorders - Other, specify	1/56 (1.8%)
Cardiac disorders
Cardiac disorders - Other, specify	1/56 (1.8%)
Sinus tachycardia	1/56 (1.8%)
Ear and labyrinth disorders
Ear and labyrinth disorders - Other, specify	1/56 (1.8%)
Ear pain	2/56 (3.6%)
External ear inflammation	1/56 (1.8%)
Middle ear inflammation	1/56 (1.8%)
Endocrine disorders
Adrenal insufficiency	3/56 (5.4%)
Cushingoid	1/56 (1.8%)
Endocrine disorders - Other, specify	2/56 (3.6%)
Hyperthyroidism	7/56 (12.5%)
Hypothyroidism	15/56 (26.8%)
Eye disorders
Blurred vision	6/56 (10.7%)
Conjunctivitis	3/56 (5.4%)
Dry eye	3/56 (5.4%)
Eye disorders - Other, specify	2/56 (3.6%)
Eye pain	1/56 (1.8%)
Eyelid function disorder	2/56 (3.6%)
Floaters	1/56 (1.8%)
Scleral disorder	1/56 (1.8%)
Watering eyes	1/56 (1.8%)
Gastrointestinal disorders
Abdominal pain	9/56 (16.1%)
Anal hemorrhage	1/56 (1.8%)
Ascites	1/56 (1.8%)
Bloating	1/56 (1.8%)
Cheilitis	1/56 (1.8%)
Colitis	3/56 (5.4%)
Constipation	16/56 (28.6%)
Diarrhea	18/56 (32.1%)
Dry mouth	3/56 (5.4%)
Dyspepsia	3/56 (5.4%)
Dysphagia	1/56 (1.8%)
Esophagitis	1/56 (1.8%)
Fecal incontinence	1/56 (1.8%)
Flatulence	1/56 (1.8%)
Gastric ulcer	1/56 (1.8%)
Gastritis	1/56 (1.8%)
Gastroesophageal reflux disease	2/56 (3.6%)
Gastrointestinal disorders - Other, specify	3/56 (5.4%)
Gastroparesis	1/56 (1.8%)
Hemorrhoids	1/56 (1.8%)
Mucositis oral	13/56 (23.2%)
Nausea	21/56 (37.5%)
Oral pain	1/56 (1.8%)
Rectal hemorrhage	3/56 (5.4%)
Rectal pain	1/56 (1.8%)
Vomiting	21/56 (37.5%)
General disorders
Chills	4/56 (7.1%)
Edema limbs	6/56 (10.7%)
Facial pain	1/56 (1.8%)
Fatigue	24/56 (42.9%)
Fever	16/56 (28.6%)
Flu like symptoms	3/56 (5.4%)
General disorders and administration site conditions - Other, specify	4/56 (7.1%)
Infusion related reaction	4/56 (7.1%)
Malaise	4/56 (7.1%)
Pain	9/56 (16.1%)
Hepatobiliary disorders
Cholecystitis	1/56 (1.8%)
Hepatobiliary disorders - Other, specify	1/56 (1.8%)
Immune system disorders
Allergic reaction	1/56 (1.8%)
Autoimmune disorder	1/56 (1.8%)
Infections and infestations
Esophageal infection	1/56 (1.8%)
Infections and infestations - Other, specify	7/56 (12.5%)
Mucosal infection	2/56 (3.6%)
Nail infection	1/56 (1.8%)
Papulopustular rash	1/56 (1.8%)
Paronychia	11/56 (19.6%)
Rash pustular	1/56 (1.8%)
Sinusitis	1/56 (1.8%)
Skin infection	1/56 (1.8%)
Upper respiratory infection	2/56 (3.6%)
Investigations
Alanine aminotransferase increased	17/56 (30.4%)
Alkaline phosphatase increased	15/56 (26.8%)
Aspartate aminotransferase increased	20/56 (35.7%)
Blood bilirubin increased	6/56 (10.7%)
Creatinine increased	1/56 (1.8%)
Hemoglobin increased	1/56 (1.8%)
INR increased	1/56 (1.8%)
Investigations - Other, specify	8/56 (14.3%)
Lipase increased	10/56 (17.9%)
Lymphocyte count decreased	21/56 (37.5%)
Neutrophil count decreased	7/56 (12.5%)
Platelet count decreased	11/56 (19.6%)
Serum amylase increased	8/56 (14.3%)
Weight loss	2/56 (3.6%)
White blood cell decreased	9/56 (16.1%)
Metabolism and nutrition disorders
Anorexia	19/56 (33.9%)
Dehydration	3/56 (5.4%)
Hypercalcemia	1/56 (1.8%)
Hyperglycemia	7/56 (12.5%)
Hyperkalemia	2/56 (3.6%)
Hypermagnesemia	1/56 (1.8%)
Hypernatremia	1/56 (1.8%)
Hypertriglyceridemia	1/56 (1.8%)
Hypoalbuminemia	14/56 (25%)
Hypocalcemia	13/56 (23.2%)
Hypoglycemia	1/56 (1.8%)
Hypokalemia	20/56 (35.7%)
Hypomagnesemia	38/56 (67.9%)
Hyponatremia	15/56 (26.8%)
Hypophosphatemia	12/56 (21.4%)
Metabolism and nutrition disorders - Other, specify	3/56 (5.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/56 (5.4%)
Arthritis	2/56 (3.6%)
Back pain	4/56 (7.1%)
Bone pain	1/56 (1.8%)
Generalized muscle weakness	2/56 (3.6%)
Musculoskeletal and connective tissue disorder - Other, specify	3/56 (5.4%)
Myalgia	4/56 (7.1%)
Pain in extremity	5/56 (8.9%)
Nervous system disorders
Akathisia	1/56 (1.8%)
Dizziness	6/56 (10.7%)
Dysesthesia	1/56 (1.8%)
Dysgeusia	3/56 (5.4%)
Dysphasia	1/56 (1.8%)
Headache	10/56 (17.9%)
Lethargy	1/56 (1.8%)
Nervous system disorders - Other, specify	1/56 (1.8%)
Peripheral motor neuropathy	1/56 (1.8%)
Peripheral sensory neuropathy	2/56 (3.6%)
Presyncope	1/56 (1.8%)
Psychiatric disorders
Anxiety	1/56 (1.8%)
Delirium	1/56 (1.8%)
Depression	3/56 (5.4%)
Insomnia	5/56 (8.9%)
Psychiatric disorders - Other, specify	2/56 (3.6%)
Renal and urinary disorders
Acute kidney injury	2/56 (3.6%)
Hematuria	3/56 (5.4%)
Renal and urinary disorders - Other, specify	1/56 (1.8%)
Renal calculi	1/56 (1.8%)
Urinary frequency	4/56 (7.1%)
Urinary retention	1/56 (1.8%)
Urinary tract pain	1/56 (1.8%)
Urinary urgency	1/56 (1.8%)
Urine discoloration	2/56 (3.6%)
Reproductive system and breast disorders
Penile pain	1/56 (1.8%)
Reproductive system and breast disorders - Other, specify	1/56 (1.8%)
Vaginal discharge	1/56 (1.8%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	2/56 (3.6%)
Cough	10/56 (17.9%)
Dyspnea	4/56 (7.1%)
Epistaxis	3/56 (5.4%)
Hiccups	2/56 (3.6%)
Hoarseness	2/56 (3.6%)
Hypoxia	2/56 (3.6%)
Nasal congestion	2/56 (3.6%)
Postnasal drip	3/56 (5.4%)
Productive cough	1/56 (1.8%)
Pulmonary hypertension	1/56 (1.8%)
Respiratory, thoracic and mediastinal disorders - Other, specify	3/56 (5.4%)
Sore throat	1/56 (1.8%)
Skin and subcutaneous tissue disorders
Dry skin	17/56 (30.4%)
Erythema multiforme	2/56 (3.6%)
Hirsutism	2/56 (3.6%)
Hyperhidrosis	1/56 (1.8%)
Hypertrichosis	1/56 (1.8%)
Nail loss	1/56 (1.8%)
Pain of skin	1/56 (1.8%)
Palmar-plantar erythrodysesthesia syndrome	3/56 (5.4%)
Photosensitivity	1/56 (1.8%)
Pruritus	27/56 (48.2%)
Rash acneiform	51/56 (91.1%)
Rash maculo-papular	7/56 (12.5%)
Scalp pain	1/56 (1.8%)
Skin and subcutaneous tissue disorders - Other, specify	12/56 (21.4%)
Skin ulceration	2/56 (3.6%)
Stevens-Johnson syndrome	1/56 (1.8%)
Surgical and medical procedures
Surgical and medical procedures - Other, specify	1/56 (1.8%)
Vascular disorders
Hypertension	21/56 (37.5%)
Hypotension	3/56 (5.4%)
Thromboembolic event	3/56 (5.4%)

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.