Phase l/II Study of Ruxolitinib for Acute Leukemia

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01251965
• Collaborator: Incyte Corporation (Industry)
• Enrollment: 27
• Location: 1
• Arms: 3
• Duration (Months): 19
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

The goal of this clinical research study is to find the highest tolerable dose of ruxolitinib that can be given to patients with acute leukemia and to learn if the study drug can help control the disease. The safety of the drug will also be studied.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: Ruxolitinib	Phase 1/Phase 2

Detailed Description

The Study Drug:

Ruxolitinib is designed to block a gene mutation that may be important in cancer cell growth and survival. By blocking the gene mutation, this may cause the cancer cells to die.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study. Up to 30 participants will be enrolled in the Phase I portion of the study, and up to 136 participants will be enrolled in Phase II.

If you are enrolled in the Phase I portion, the dose of ruxolitinib you receive will depend on when you joined this study. The first group of participants will receive the lowest dose level of ruxolitinib. Each new group will receive a higher dose of ruxolitinib than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of ruxolitinib is found.

If you are enrolled in the Phase II portion, you will receive ruxolitinib at the highest dose that was tolerated in the Phase I portion or at a lower dose.

Study Drug Administration:

You will take ruxolitinib tablet(s) by mouth 2 times a day on Days 1-28 of each 28-day study cycle.

You will be asked to keep a diary to record the doses taken. You will be asked to bring your diary and any unused drug to your next visit.

Study Visits:

On Days 1, 7, 14, and 21 of Cycle 1:

• You will have a physical exam.

• Blood (about 2 teaspoons) will be drawn for routine tests.

• You will be asked about any treatments you may have had, any other drugs you may be taking, and any side effects you may be having.

• On Day 14 only, you will have a bone marrow aspiration performed to check the status of the disease.

On Day 1 of Cycle 2:

• You will have a physical exam.

• You will be asked about any treatments you may have had, any other drugs you may be taking, and any side effects you may be having.

• Blood (about 2 teaspoons) will be drawn for routine tests.

• You will have a bone marrow aspiration performed to check the status of the disease.

During Cycles 2 and beyond, blood (about 2 teaspoons) will be drawn for routine tests at least every 1-2 weeks. This blood may be drawn at a clinic close to your home.

On Day 1 of Cycles 3, 6, 9, and beyond:

• You will have a physical exam.

• You will be asked about any treatments you may have had, any other drugs you may be taking, and any side effects you may be having.

• Blood (about 2 teaspoons) will be drawn for routine tests.

• You will have a bone marrow aspiration performed to check the status of the disease. On Day 1 of Cycle 3, this will only be done if your doctor thinks it is needed.

Length of Study:

You may continue taking the study drug for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse or intolerable side effects occur.

Your participation on the study will be over once you have completed the end-of-study visit and the follow-up call.

End-of-Study Visit:

After your last dose of study drug, you will have an end-of-study visit. At this visit, the following tests and procedures will be performed:

• You will have a physical exam.

• You will be asked about any treatments you may have had, any other drugs you may be taking, and any side effects you may be having.

• Blood (about 2 teaspoons) will be drawn for routine tests.

• You will have a bone marrow aspiration performed to check the status of the disease.

Follow-Up:

About one month after your end-of-study visit, the study staff will call and ask about any side effects you may be having. This call should last about 5 minutes.

This is an investigational study. Ruxolitinib is FDA approved and commercially available for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera (post-PV) myelofibrosis and post-essential thrombocythemia (post-ET) myelofibrosis. Its use to treat acute leukemia is investigational.

Up to 166 patients will take part in this study. All will be enrolled at MD Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Intervention Model Description: Phase I is a standard 3+3 design and will be used to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD), and no formal evaluation of efficacy (response rate will be implemented. Patients in Phase I part who were treated at the MTD will be included toward patients assessed for response in the phase II stage.Phase I is a standard 3+3 design and will be used to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD), and no formal evaluation of efficacy (response rate will be implemented. Patients in Phase I part who were treated at the MTD will be included toward patients assessed for response in the phase II stage.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study to Determine the Safety and Efficacy of Ruxolitinib, a JAK1/JAK2 Inhibitor, in Subjects With Relapsed or Refractory Acute Leukemia
• Study Start Date: Dec 1, 2010
• Actual Primary Completion Date: Jul 1, 2012
• Actual Study Completion Date: Jul 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ruxolitinib 50 mg BID Phase I - Starting dose of Ruxolitinib 50 mg by mouth twice a day for 28 day cycle.	Drug: Ruxolitinib; Phase I - Starting dose of 50 mg by mouth twice a day for 28 day cycle. Phase II - MTD reached in Phase I.; Other Names: Jakafi INCBO18424 INC424
Experimental: Ruxolitinib 100 mg BID Phase I dose of Ruxolitinib 100 mg by mouth twice a day for 28 day cycle.	Drug: Ruxolitinib; Phase I - Starting dose of 50 mg by mouth twice a day for 28 day cycle. Phase II - MTD reached in Phase I.; Other Names: Jakafi INCBO18424 INC424
Experimental: Ruxolitinib 200 mg BID Phase I dose of Ruxolitinib 200 mg by mouth twice a day for 28 day cycle.	Drug: Ruxolitinib; Phase I - Starting dose of 50 mg by mouth twice a day for 28 day cycle. Phase II - MTD reached in Phase I.; Other Names: Jakafi INCBO18424 INC424

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose Limiting Toxicities (DLTs) [End of first 28 day cycle for toxicity]

   MTD defined as highest dose level at which no more than one out of six subject experiences dose limiting toxicity (DLT) during first cycle (28 days) of therapy. A non-hematologic DLT defined as a clinically significant grade 3 or 4 adverse event or abnormal laboratory value (according to Common Toxicity Criteria for Adverse Effects (CTCAE) criteria) assessed as related to study drug (and unrelated to disease progression, intercurrent illness, or concomitant medications) occurring during first 28 days on study. Participants who received at least 80% of the originally assigned doses in the first cycle were evaluable for DLT assessment of each cohort.

2. Maximum Tolerated Dose (MTD) of Ruxolitinib [End of first 28 day cycle]

   The MTD is defined as the highest dose level at which no more than one out of six subject experiences DLT during the first cycle (28 days) of therapy.

Secondary Outcome Measures

1. Participants With a Response [Up to 1 year]

   Response is defined as complete remission (CR) + complete remission with incomplete blood count (CRi) + Hematologic improvement (HI). Response was to be assessed for participants who were evaluated for the Phase II portion of this study. CR is absolute neutrophil count (ANC) >/= 1x109/L and platelet count >/= 100x109/L, absence of leukemia blast cells, normal marrow differential, and complete resolution of extramedullary disease. CRi is CR but platelets are < 100x109/L or ANC is <1x109/L. HI is described by the number of individual, positively affected cell lines without the use of growth factors and/or transfusions (lasting at least 4 weeks).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 14 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Must be >14 years of age

2. Must be diagnosed with refractory or relapsed AML or ALL.

3. Must have adequate organ function as demonstrated by the following: o Alanine Aminotransferase (ALT) (SGOT) and/or Aspartate Aminotransferase (AST) (SGPT) equal to or less than 1.5x upper limit of normal o Serum creatinine equal to or less than 2.5 mg/dL

4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2

5. At least 2 weeks from prior leukemia-directed treatment to starting treatment drug (except for hydroxyurea, which is allowed if clinically indicated but should be stopped after 2 weeks of receiving study drug, and glucocorticoids, which are allowed but should be stopped upon starting treatment drug).

6. Treatment-related toxicities from prior therapies must have resolved to Grade equal to or less than 1 (except for peripheral neuropathy, which should resolve to grade equal to or less than 2)

7. No active malignancies with the exception of basal cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast.

8. Females of childbearing potential (FCBP)(A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) must have negative pregnancy test. FCBP and males participating in the study must agree to use a reliable form of contraception or to practice complete abstinence from heterosexual intercourse while participating in the study and for at least 28 days after discontinuation from the study. If pregnancy or a positive pregnancy test does occur in a study subject, treatment with the study drug must be immediately discontinued.

Exclusion Criteria:

1. Known positive status for HIV, or known active hepatitis A, B, or C infection.

2. Any serious medical condition or psychiatric illness that would prevent, (as judged by the treating physician) the subject from signing the informed consent form or any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.

3. Pregnant or lactating females.

4. Acute promyelocytic leukemia

5. Concurrent use of strong inducers or strong inhibitors of cytochrome P450 3A4 (CYP3A4). Strong inducers are rifampin and St. John's Worth. Strong inhibitors are HIV-antivirals, clarythromycin, itraconazole, ketoconazole, nefazodone, and telithromycin.

6. Participating in any other research trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• Incyte Corporation

Investigators

• Principal Investigator: Srdan Verstovsek, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT01251965
• Other Study ID Numbers: 2010-0450; NCI-2011-02439
• First Posted: Dec 2, 2010
• Last Update Posted: Sep 6, 2019
• Last Verified: Sep 1, 2019

• Keywords provided by M.D. Anderson Cancer Center: Relapsed Acute Leukemia; Acute myeloid leukemia; AML; Acute lymphocytic leukemia; ALL; Ruxolitinib; Jakafi; INC424; INCB018424
• Additional relevant MeSH terms: Leukemia

Study Results

Participant Flow

Recruitment Details	Recruitment Period: December 9, 2010 to September 26, 2012. All recruitment done at The University of Texas (UT) MD Anderson Cancer Center.

Arm/Group Title	Ruxolitinib 50 mg BID	Ruxolitinib 100 mg BID	Ruxolitinib 200 mg BID
Arm/Group Description	Phase I starting dose of Ruxolitinib 50 mg by mouth twice a day (BID) for 28 day cycle.	Phase I dose of Ruxolitinib 100 mg by mouth twice a day for 28 day cycle.	Phase I dose of Ruxolitinib 200 mg by mouth twice a day for 28 day cycle.
Period Title: Overall Study
STARTED	4	5	18
COMPLETED	3	3	7
NOT COMPLETED	1	2	11

Baseline Characteristics

Arm/Group Title	Ruxolitinib 50 mg BID	Ruxolitinib 100 mg BID	Ruxolitinib 200 mg BID	Total
Arm/Group Description	Phase I starting dose of Ruxolitinib 50 mg by mouth twice a day (BID) for 28 day cycle.	Phase I dose of Ruxolitinib 100 mg by mouth twice a day for 28 day cycle.	Phase I dose of Ruxolitinib 200 mg by mouth twice a day for 28 day cycle.	Total of all reporting groups
Overall Participants	4	5	18	27
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	66	70	71	69
Sex: Female, Male (Count of Participants)
Female	3 75%	1 20%	9 50%	13 48.1%
Male	1 25%	4 80%	9 50%	14 51.9%
Region of Enrollment (Count of Participants)
United States	4 100%	5 100%	18 100%	27 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities (DLTs)
Description	MTD defined as highest dose level at which no more than one out of six subject experiences dose limiting toxicity (DLT) during first cycle (28 days) of therapy. A non-hematologic DLT defined as a clinically significant grade 3 or 4 adverse event or abnormal laboratory value (according to Common Toxicity Criteria for Adverse Effects (CTCAE) criteria) assessed as related to study drug (and unrelated to disease progression, intercurrent illness, or concomitant medications) occurring during first 28 days on study. Participants who received at least 80% of the originally assigned doses in the first cycle were evaluable for DLT assessment of each cohort.
Time Frame	End of first 28 day cycle for toxicity

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ruxolitinib 50 mg BID	Ruxolitinib 100 mg BID	Ruxolitinib 200 mg BID
Arm/Group Description	Phase I starting dose of Ruxolitinib 50 mg by mouth twice a day (BID) for 28 day cycle.	Phase I dose of Ruxolitinib 100 mg by mouth twice a day for 28 day cycle.	Phase I dose of Ruxolitinib 200 mg by mouth twice a day for 28 day cycle.
Measure Participants	3	3	7
Count of Participants [Participants]	0 0%	0 0%	0 0%

2. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Ruxolitinib
Description	The MTD is defined as the highest dose level at which no more than one out of six subject experiences DLT during the first cycle (28 days) of therapy.
Time Frame	End of first 28 day cycle

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ruxolitinib
Arm/Group Description	Phase I - Starting dose of Ruxolitinib 50 mg by mouth twice a day for 28 day cycle. Phase II - MTD reached in Phase I. Ruxolitinib: Phase I - Starting dose of 50 mg by mouth twice a day for 28 day cycle. Phase II - MTD reached in Phase I.
Measure Participants	13
Number [mg]	NA

3. Secondary Outcome

Title	Participants With a Response
Description	Response is defined as complete remission (CR) + complete remission with incomplete blood count (CRi) + Hematologic improvement (HI). Response was to be assessed for participants who were evaluated for the Phase II portion of this study. CR is absolute neutrophil count (ANC) >/= 1x109/L and platelet count >/= 100x109/L, absence of leukemia blast cells, normal marrow differential, and complete resolution of extramedullary disease. CRi is CR but platelets are < 100x109/L or ANC is <1x109/L. HI is described by the number of individual, positively affected cell lines without the use of growth factors and/or transfusions (lasting at least 4 weeks).
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

The study was stopped because of a lack of satisfactory clinical benefit, and did not go on to the Phase II portion. Therefore, data were not collected for this outcome measure.

Arm/Group Title	Ruxolitinib 50 mg BID	Ruxolitinib 100 mg BID	Ruxolitinib 200 mg BID
Arm/Group Description	Phase I starting dose of Ruxolitinib 50 mg by mouth twice a day (BID) for 28 day cycle.	Phase I dose of Ruxolitinib 100 mg by mouth twice a day for 28 day cycle.	Phase I dose of Ruxolitinib 200 mg by mouth twice a day for 28 day cycle.
Measure Participants	0	0	0

Adverse Events

Time Frame	Adverse events collected during 28 day cycle, up to 9 cycles.
Arm/Group Title	Ruxolitinib 50 mg BID		Ruxolitinib 100 mg BID		Ruxolitinib 200 mg BID
Arm/Group Description	Phase I starting dose of Ruxolitinib 50 mg by mouth twice a day (BID) for 28 day cycle.		Phase I dose of Ruxolitinib 100 mg by mouth twice a day for 28 day cycle.		Phase I dose of Ruxolitinib 200 mg by mouth twice a day for 28 day cycle.
All Cause Mortality
	Ruxolitinib 50 mg BID		Ruxolitinib 100 mg BID		Ruxolitinib 200 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ruxolitinib 50 mg BID		Ruxolitinib 100 mg BID		Ruxolitinib 200 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		5/5 (100%)		18/18 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	0/4 (0%)		0/5 (0%)		1/18 (5.6%)
Thrombocytopenia	1/4 (25%)		0/5 (0%)		0/18 (0%)
Cardiac disorders
Tachycardia	0/4 (0%)		0/5 (0%)		1/18 (5.6%)
Gastrointestinal disorders
Abdominal pain	0/4 (0%)		0/5 (0%)		1/18 (5.6%)
General disorders
Death	0/4 (0%)		0/5 (0%)		11/18 (61.1%)
Fever	1/4 (25%)		1/5 (20%)		1/18 (5.6%)
Pain	1/4 (25%)		0/5 (0%)		0/18 (0%)
Investigations
Neutropenia	1/4 (25%)		0/5 (0%)		0/18 (0%)
Metabolism and nutrition disorders
Dehydration	0/4 (0%)		1/5 (20%)		0/18 (0%)
Nervous system disorders
Cerebral edema and mass	1/4 (25%)		0/5 (0%)		0/18 (0%)
Headache	0/4 (0%)		0/5 (0%)		1/18 (5.6%)
Stroke	0/4 (0%)		0/5 (0%)		2/18 (11.1%)
Respiratory, thoracic and mediastinal disorders
Alveolar hemorrhage	1/4 (25%)		0/5 (0%)		0/18 (0%)
Dyspnea	0/4 (0%)		0/5 (0%)		1/18 (5.6%)
Hemoptysis	3/4 (75%)		1/5 (20%)		0/18 (0%)
Hypoxia	0/4 (0%)		0/5 (0%)		2/18 (11.1%)
Mucositis	0/4 (0%)		0/5 (0%)		1/18 (5.6%)
Pneumonia	2/4 (50%)		3/5 (60%)		1/18 (5.6%)
Respiratory failure	1/4 (25%)		0/5 (0%)		2/18 (11.1%)
Skin and subcutaneous tissue disorders
Skin ulceration	1/4 (25%)		0/5 (0%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	Ruxolitinib 50 mg BID		Ruxolitinib 100 mg BID		Ruxolitinib 200 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		5/5 (100%)		18/18 (100%)
Cardiac disorders
Ventricular arrhythmia	0/4 (0%)		0/5 (0%)		2/18 (11.1%)
Gastrointestinal disorders
Constiptation	0/4 (0%)		0/5 (0%)		1/18 (5.6%)
Diarrhea	0/4 (0%)		0/5 (0%)		1/18 (5.6%)
Mucositis	0/4 (0%)		0/5 (0%)		3/18 (16.7%)
Nausea	1/4 (25%)		0/5 (0%)		0/18 (0%)
General disorders
Fatigue	1/4 (25%)		1/5 (20%)		1/18 (5.6%)
Edema: head and neck	1/4 (25%)		0/5 (0%)		2/18 (11.1%)
Edema: limb	0/4 (0%)		0/5 (0%)		1/18 (5.6%)
Pain	1/4 (25%)		0/5 (0%)		2/18 (11.1%)
Infections and infestations
Infections	4/4 (100%)		2/5 (40%)		18/18 (100%)
Investigations
Hemoglobin Increased	1/4 (25%)		1/5 (20%)		0/18 (0%)
Neutrophils count decreased	2/4 (50%)		2/5 (40%)		6/18 (33.3%)
Platelets decreased	2/4 (50%)		3/5 (60%)		6/18 (33.3%)
Alkaline phosphatase Increased	1/4 (25%)		0/5 (0%)		0/18 (0%)
Alanine aminotransferase increased (ALT)	1/4 (25%)		2/5 (40%)		4/18 (22.2%)
Aspartate aminotransferase increased (AST)	1/4 (25%)		1/5 (20%)		2/18 (11.1%)
Blood bilirubin increased	0/4 (0%)		2/5 (40%)		1/18 (5.6%)
Creatinine Increased	1/4 (25%)		2/5 (40%)		4/18 (22.2%)
Metabolism and nutrition disorders
Hypercalcemia	1/4 (25%)		0/5 (0%)		0/18 (0%)
Musculoskeletal and connective tissue disorders
Muscle weakness	0/4 (0%)		2/5 (40%)		1/18 (5.6%)
Nervous system disorders
Central Nervous System Ischemia	1/4 (25%)		0/5 (0%)		2/18 (11.1%)
Dizziness	0/4 (0%)		0/5 (0%)		1/18 (5.6%)
Neurology-Other Issues	0/4 (0%)		0/5 (0%)		1/18 (5.6%)
Speech impairment	0/4 (0%)		0/5 (0%)		1/18 (5.6%)
Tremor	0/4 (0%)		0/5 (0%)		1/18 (5.6%)
Reproductive system and breast disorders
Hot Flash	0/4 (0%)		0/5 (0%)		1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Hemorrhage pulmonary	1/4 (25%)		1/5 (20%)		0/18 (0%)
Dyspnea	0/4 (0%)		1/5 (20%)		0/18 (0%)
Pleural effusion	0/4 (0%)		0/5 (0%)		1/18 (5.6%)
PULMONARY INFILTRATES	0/4 (0%)		0/5 (0%)		1/18 (5.6%)
Skin and subcutaneous tissue disorders
Rash	0/4 (0%)		0/5 (0%)		1/18 (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.