Open-label, Phase II Study of MLN9708 in Patients With Relapsed/Refractory Cutaneous and Peripheral T-cell Lymphomas

• Sponsor: University of Michigan Rogel Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02158975
• Collaborator: (none)
• Enrollment: 13
• Location: 1
• Arm: 1
• Duration (Months): 26
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Historically cutaneous and peripheral T-cell lymphomas have response rates of approximately 30% to standard chemotherapy regimens. We alternatively hypothesize that MLN9708 will be active in this disease and will improve best objective response.

We will also determine the extent to which MLN9708 inhibits GATA-3 (Trans-acting T-cell-specific transcription factor) expression, which is associated with poor prognosis, and whether GATA-3 expression represents a novel predictive biomarker for MLN9708 sensitivity.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, T-Cell	Drug: MLN9708	Phase 2

Detailed Description

Up to 25 patients meeting the inclusion and exclusion criteria will be enrolled into this trial in two stages. All enrolled patients will be treated with MLN9708 4 mg PO weekly (days 1, 8, 15 every 28 days) until disease progression or unacceptable toxicity. In the initial stage of the study a total of 11 patients will be enrolled and treated with MLN9708. Should at least 4 patients exhibit a response (CR/CRu, PR), the second stage of 14 patients will open for enrollment. Efficacy will be assessed radiographically, by peripheral blood and bone marrow examination (when indicated), and physical exam every 8 weeks. Safety will be assessed by periodic physical exams, laboratory studies, and adverse events. All patients will have a follow-up visit 35 days (+/-7 days) following the last study drug treatment. Patients with accessible tumor tissue will be asked to undergo a biopsy for a fresh tissue sample for assessment of GATA-3 expression. Archived tissue samples from the initial diagnostic biopsy and the most recent lymphoma biopsy will be obtained in the event a fresh tumor biopsy cannot be obtained. Patients with GATA-3+ TCL and accessible tumor tissue will undergo a tumor biopsy at day 21 (+/- 7 days) of cycle 1. All baseline fresh or archived tissue will undergo central pathology review to confirm the diagnosis of TCL. The rationale for proteasome inhibition in T-cell lymphomas, based on the pre-clinical (and previous phase II) data, is compelling. Therefore, this phase II study will not be restricted to patients with GATA-3 expressing lymphomas.

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-label, Single-center Phase II Study of MLN9708 (Ixazomib) in Patients With Relapsed/Refractory Cutaneous and Peripheral T-cell Lymphomas
• Study Start Date: Sep 1, 2014
• Actual Primary Completion Date: Oct 1, 2016
• Actual Study Completion Date: Nov 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MLN9708 MLN9708 4mg by mouth weekly (days 1, 8, 15) every 28 days.	Drug: MLN9708

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate [Up to 24 months after initiation of study treatment]

   The percentage of patients with an objective response rate will be determined. The overall response will be based on response in each compartment (skin, blood, lymph nodes and viscera) using a global composite scoring system. Objective response is considered (CR) Complete Response (Complete disappearance of all clinical evidence of disease), CRu (Complete Response Unconfirmed), or (PR) Partial Response (Regression of measurable disease).

Secondary Outcome Measures

1. Number Patients That Experience Adverse Events, Grades 3-5 [30 days after the last dose of study drug]

   To assess the safety and tolerability of MLN9708, the number of patients experiencing Adverse Events (AEs) greater than or equal to grade 3 will be recorded.

2. Median Progression Free Survival Time [24 months after initiation of study treatment]

   Progression Free Survival (PFS) is defined as the time from study start until disease progression or death.

3. Median Overall Survival Time [24 months after initiation of study treatment]

   Overall Survival (OS) is defined as the time from study start until death.

4. Duration of Response [24 months after initiation of study treatment]

   Time from documentation of tumor response to disease progression.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female patients 18 years or older at the time of enrollment.

• Voluntary written consent must be given.

• Female patients who are postmenopausal for at least 1 year before the screening visit, OR surgically sterile, OR agree to practice 2 effective methods of contraception, at the same time, through 90 days after the last dose of study drug, AND adhere to the guidelines of any treatment-specific pregnancy prevention program, OR agree to practice true abstinence.

• Male patients must agree to practice effective barrier contraception through 90 days after the last dose of study drug, OR adhere to the guidelines of any treatment-specific pregnancy prevention program, OR agree to practice true abstinence.

• Patients must have histologically proven T-cell lymphoma, including Peripheral T-cell lymphoma, Angioimmunoblastic T-cell lymphoma, Anaplastic large cell lymphoma (ALK positive), Anaplastic large cell lymphoma (ALK negative), Mycosis fungoides, Sezary syndrome.

• CTCL patients must have stage IIb-IV disease.

• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.

• Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count ≥ 75,000/mm3.

• Platelet transfusions are not allowed within 3 days before study enrollment.

• Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN).

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ to 3 x ULN.

• Creatinine clearance ≥30 mL/min.

• Documented disease progression after receiving at least one prior therapeutic regimen.

Exclusion Criteria:

• Female patients who are lactating or have a positive serum pregnancy test.

• Failure to have recovered (ie, less than or equal to Grade 1 toxicity) from the reversible effects of prior chemotherapy.

• Major surgery within 14 days of enrollment.

• Radiotherapy within 14 days of enrollment. If the field is small, 7 days will be considered a sufficient interval between treatment and administration of the MLN9708.

• Known central nervous system involvement.

• Infection requiring systemic intravenous antibiotic therapy or other serious infection within 7 days before study enrollment.

• Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.

• Systemic treatment, within 14 days before the first dose of MLN9708, with strong inhibitors of CYP1A2, strong inhibitors of CYP3A or strong CYP3A inducers or use of Ginkgo biloba or St. John's wort.

• Ongoing or active systemic infection, active hepatitis B or C virus infection, or HIV positive.

• Any serious medical or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol.

• Known allergy to any of the study medications, their analogues, or excipients.

• Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 including difficulty swallowing.

• Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.

• Patient has greater than or equal to Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period.

• Participation in other clinical trials with other investigational agents not included in this trial, within 21days of the start of this trial and throughout the duration of this trial.

• Prior allogeneic hematopoietic stem cell transplant.

• Prior autologous hematopoietic stem cell transplant within 90 days of study entry.

• Prior treatment with bortezomib.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan Hospital	Ann Arbor	Michigan	United States	48109

Sponsors and Collaborators

• University of Michigan Rogel Cancer Center

Investigators

• Principal Investigator: Ryan Wilcox, M.D., Ph.D., University of Michigan Rogel Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT02158975
• Other Study ID Numbers: UMCC 2014.031; HUM00088647
• First Posted: Jun 9, 2014
• Last Update Posted: Nov 13, 2017
• Last Verified: Oct 1, 2017

• Additional relevant MeSH terms: Lymphoma; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Ixazomib

Study Results

Participant Flow

Arm/Group Title	MLN9708
Arm/Group Description	MLN9708 4mg by mouth weekly (days 1, 8, 15) every 28 days. MLN9708
Period Title: Overall Study
STARTED	13
COMPLETED	12
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	MLN9708
Arm/Group Description	MLN9708 4mg by mouth weekly (days 1, 8, 15) every 28 days. MLN9708
Overall Participants	12
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	70
Sex: Female, Male (Count of Participants)
Female	3 25%
Male	9 75%
T-Cell Lymphoma Subtype (Count of Participants)
Cutaneous T-cell Lymphoma (CTCL)	5 41.7%
Peripheral T-cell Lymphoma (PTCL)	7 58.3%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate
Description	The percentage of patients with an objective response rate will be determined. The overall response will be based on response in each compartment (skin, blood, lymph nodes and viscera) using a global composite scoring system. Objective response is considered (CR) Complete Response (Complete disappearance of all clinical evidence of disease), CRu (Complete Response Unconfirmed), or (PR) Partial Response (Regression of measurable disease).
Time Frame	Up to 24 months after initiation of study treatment

Outcome Measure Data

Analysis Population Description

12 analyzable patients

Arm/Group Title	MLN9708
Arm/Group Description	MLN9708 4mg by mouth weekly (days 1, 8, 15) every 28 days. MLN9708
Measure Participants	12
Number (95% Confidence Interval) [percentage of patients]	8

2. Secondary Outcome

Title	Number Patients That Experience Adverse Events, Grades 3-5
Description	To assess the safety and tolerability of MLN9708, the number of patients experiencing Adverse Events (AEs) greater than or equal to grade 3 will be recorded.
Time Frame	30 days after the last dose of study drug

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MLN9708
Arm/Group Description	MLN9708 4mg by mouth weekly (days 1, 8, 15) every 28 days. MLN9708
Measure Participants	12
Anemia	1 8.3%
Thrombocytopenia	1 8.3%
Diarrhea	1 8.3%
Mucocitis	1 8.3%
Acute Kidney Injury	1 8.3%
Atrial Fibrilation	1 8.3%
Dyspnea	1 8.3%
Hypercalcemia	1 8.3%
Hyponatremia	1 8.3%
Hypotension	1 8.3%
Lymph Node Pain	1 8.3%
Rash	1 8.3%
Respiratory Failure	1 8.3%
Supraventricular Tachycardia	1 8.3%
Thromboembolic Event	1 8.3%

3. Secondary Outcome

Title	Median Progression Free Survival Time
Description	Progression Free Survival (PFS) is defined as the time from study start until disease progression or death.
Time Frame	24 months after initiation of study treatment

Outcome Measure Data

Analysis Population Description

5 of the 12 patients withdrew prior to progression and therefore progression free survival was censored at their time of withdraw.

Arm/Group Title	MLN9708
Arm/Group Description	MLN9708 4mg by mouth weekly (days 1, 8, 15) every 28 days. MLN9708
Measure Participants	12
Median (95% Confidence Interval) [months]	3.2

4. Secondary Outcome

Title	Median Overall Survival Time
Description	Overall Survival (OS) is defined as the time from study start until death.
Time Frame	24 months after initiation of study treatment

Outcome Measure Data

Analysis Population Description

Five patients died between start of treatment and database lock. Patients who were alive at the time of the database lock (March 31st, 2017) were administratively censored.

Arm/Group Title	MLN9708
Arm/Group Description	MLN9708 4mg by mouth weekly (days 1, 8, 15) every 28 days. MLN9708
Measure Participants	12
Median (95% Confidence Interval) [months]	NA

5. Secondary Outcome

Title	Duration of Response
Description	Time from documentation of tumor response to disease progression.
Time Frame	24 months after initiation of study treatment

Outcome Measure Data

Analysis Population Description

Although 12 patients were analyzable, only one patient responded to treatment and therefore only 1 patient is represented for the duration of response.

Arm/Group Title	MLN9708
Arm/Group Description	MLN9708 4mg by mouth weekly (days 1, 8, 15) every 28 days.
Measure Participants	1
Number [months]	12

Adverse Events

Arm/Group Title	MLN9708
Arm/Group Description	MLN9708 4mg by mouth weekly (days 1, 8, 15) every 28 days.
All Cause Mortality
	MLN9708
	Affected / at Risk (%)	# Events
Total	1/12 (8.3%)
Serious Adverse Events
	MLN9708
	Affected / at Risk (%)	# Events
Total	8/12 (66.7%)
Blood and lymphatic system disorders
Anemia	1/12 (8.3%)	1
Cardiac disorders
Atrial fibrillation	1/12 (8.3%)	1
Hypotension	1/12 (8.3%)	1
Supraventricular tachycardia	1/12 (8.3%)	1
Gastrointestinal disorders
Diarrhea	1/12 (8.3%)	1
Infections and infestations
Sepsis	1/12 (8.3%)	1
Investigations
Platelet count decreased	1/12 (8.3%)	1
Rash maculo-papular	1/12 (8.3%)	1
Metabolism and nutrition disorders
Hypercalcemia	1/12 (8.3%)	1
Renal and urinary disorders
Acute kidney injury	1/12 (8.3%)	1
Renal and urinary disorders - Other, specify	1/12 (8.3%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/12 (8.3%)	1
Respiratory failure	1/12 (8.3%)	1
Vascular disorders
Thromboembolic event	1/12 (8.3%)	2
Other (Not Including Serious) Adverse Events
	MLN9708
	Affected / at Risk (%)	# Events
Total	10/12 (83.3%)
Blood and lymphatic system disorders
Lymph node pain	1/12 (8.3%)	1
Endocrine disorders
Hypothyroidism	1/12 (8.3%)	1
Gastrointestinal disorders
Abdominal pain	1/12 (8.3%)	2
Constipation	2/12 (16.7%)	2
Dysgeusia	1/12 (8.3%)	1
Mucositis oral	1/12 (8.3%)	1
Nausea	2/12 (16.7%)	2
Vomiting	3/12 (25%)	3
General disorders
Chills	1/12 (8.3%)	1
Edema limbs	2/12 (16.7%)	2
Fatigue	2/12 (16.7%)	2
Infections and infestations
Skin infection	1/12 (8.3%)	1
Upper respiratory infection	2/12 (16.7%)	3
Investigations
Alanine aminotransferase increased	1/12 (8.3%)	1
Aspartate aminotransferase increased	2/12 (16.7%)	2
Metabolism and nutrition disorders
Anorexia	1/12 (8.3%)	1
Hyponatremia	1/12 (8.3%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	1/12 (8.3%)	1
Back pain	2/12 (16.7%)	2
Pain in extremity	1/12 (8.3%)	1
Nervous system disorders
Dysarthria	1/12 (8.3%)	1
Peripheral sensory neuropathy	3/12 (25%)	5
Skin and subcutaneous tissue disorders
Pruritus	2/12 (16.7%)	2
Rash acneiform	1/12 (8.3%)	1
Skin ulceration	1/12 (8.3%)	1

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.