Waldenstrom's Macroglobulinemia
Conditions
Brief summary
Recent reports have identified a specific oncogenic mutation L265P of the MYD88 gene in approximately 90% of the patients with Waldenström's macroglobulinemia. MYD88 is a key linker protein in the signaling pathway of Toll Like Receptors (TLRs) 7, 8, and 9, and IMO-8400 is an oligonucleotide specifically designed to inhibit TLRs 7,8, and 9. The scientific hypothesis for use of IMO-8400 to treat patients with Waldenström's macroglobulinemia depends on the inhibition of mutant MYD88 signaling in the TLR pathway, thereby interrupting the proliferation of cell populations responsible for the propagation of the disease.
Detailed description
Eligible subjects will be enrolled and assigned to escalating dose cohorts. Treatment will be administered by subcutaneous injection.
Interventions
DRUGIMO-8400
IMO-8400 at escalating dose levels by subcutaneous injection
Sponsors
Idera Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients must have a diagnosis of relapsed Waldenstrom's Macroglobulinemia. In addition to the above, key inclusion and
Exclusion criteria
are listed below. Inclusion Criteria: 1. At least 18 years of age. 2. Agree to use contraception 3. Hemoglobin ≥ 7.5 g/dL, - Absolute neutrophil count ≥ 1.0 x 109/L (1000/mm3), - Platelets ≥ 50,000/μL
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | Up to 24 weeks | Safety and tolerability of IMO-8400 in patients with Waldenstrom's Macroglobulinemia: Assessment of adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response | Up to 24 weeks | Best Overall Response using criteria from the VIth International Workshop in Waldenstrom's Macroglobulinemia |
| Identify the Number of Patients Experiencing DLTs at Each Dose Level | 28 days | To identify an appropriate dose of IMO-8400 for further clinical evaluation via evaluation of DLT at each dose level |
| Pharmacokinetics of Escalating Dose Levels of IMO 8400 Administered by SC Injection - Cmax. | Cycle 1 Week 1 Day 1: Samples were obtained pre-dose (within 1 hr prior to injection) and post-dose at 1 hr (+/-5 min), 2 hrs (+/-10 min) and 4 hrs (+/-15 min) | Pharmacokinetics of escalating dose levels of IMO 8400 administered by SC injection - Cmax. |
| Pharmacokinetics of Escalating Dose Levels of IMO 8400 Administered by SC Injection - AUC0-t (hr*ng/mL) | Cycle 1 Week 1 Day 1: Samples were obtained pre-dose (within 1 hr prior to injection) and post-dose at 1 hr (+/-5 min), 2 hrs (+/-10 min) and 4 hrs (+/-15 min) | Pharmacokinetics of escalating dose levels of IMO 8400 administered by SC injection - AUC0-t (hr\*ng/mL) . |
Countries
United States
Participant flow
Recruitment details
Patients were enrolled from 02 April 2014 through 31 March 2017 at 14 study sites in the United States.
Pre-assignment details
Screening occurred ≤ 21 days before Day 1 (the first injection of study drug).
Participants by arm
| Arm | Count |
|---|---|
| IMO-8400 0.6 mg/kg 1x/wk IMO-8400 0.6 mg/kg once weekly s.c. | 6 |
| IMO-8400 1.2 mg/kg 1x/wk IMO-8400 1.2 mg/kg once weekly s.c. | 5 |
| IMO-8400 1.2 mg/kg 2x/wk IMO-8400 1.2 mg/kg twice weekly s.c. | 14 |
| IMO-8400 2.4 mg/kg 1x/wk IMO-8400 2.4 mg/kg once weekly s.c. | 6 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 4 | 2 |
| Overall Study | Lack of Efficacy | 0 | 2 | 1 | 0 |
| Overall Study | Miscellaneous | 1 | 1 | 2 | 1 |
| Overall Study | Study terminated by Sponsor | 0 | 0 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | IMO-8400 0.6 mg/kg 1x/wk | Total | IMO-8400 2.4 mg/kg 1x/wk | IMO-8400 1.2 mg/kg 2x/wk | IMO-8400 1.2 mg/kg 1x/wk |
|---|---|---|---|---|---|
| Age, Continuous | 74.8 years STANDARD_DEVIATION 12.92 | 68.0 years STANDARD_DEVIATION 11.53 | 62.7 years STANDARD_DEVIATION 11.36 | 66.5 years STANDARD_DEVIATION 11.17 | 70.4 years STANDARD_DEVIATION 9.71 |
| Baseline IPSSWM Score High | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants |
| Baseline IPSSWM Score Intermediate | 3 Participants | 18 Participants | 4 Participants | 8 Participants | 3 Participants |
| Baseline IPSSWM Score Low | 2 Participants | 10 Participants | 2 Participants | 5 Participants | 1 Participants |
| Baseline Monoclonal IgM | 1.04 g/dL STANDARD_DEVIATION 0.64 | 1.37 g/dL STANDARD_DEVIATION 0.773 | 1.62 g/dL STANDARD_DEVIATION 0.741 | 1.57 g/dL STANDARD_DEVIATION 0.835 | 0.93 g/dL STANDARD_DEVIATION 0.614 |
| Baseline Total IgM | 1090 mg/dL | 2715 mg/dL STANDARD_DEVIATION 1473 | 2910 mg/dL STANDARD_DEVIATION 1727 | 2857 mg/dL STANDARD_DEVIATION 1567 | 2410 mg/dL STANDARD_DEVIATION 973 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 31 Participants | 6 Participants | 14 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 28 Participants | 5 Participants | 12 Participants | 5 Participants |
| Region of Enrollment United States | 6 participants | 31 participants | 6 participants | 14 participants | 5 participants |
| Sex: Female, Male Female | 2 Participants | 9 Participants | 1 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 4 Participants | 22 Participants | 5 Participants | 11 Participants | 2 Participants |
| Time Since WM Diagnosis (yrs) | 7.03 years STANDARD_DEVIATION 4.62 | 7.58 years STANDARD_DEVIATION 4.66 | 5.78 years STANDARD_DEVIATION 5.22 | 7.66 years STANDARD_DEVIATION 3.55 | 10.16 years STANDARD_DEVIATION 6.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 5 | 0 / 14 | 0 / 6 |
| other Total, other adverse events | 6 / 6 | 5 / 5 | 13 / 14 | 6 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 5 | 1 / 14 | 2 / 6 |
Outcome results
Primary
Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia
Safety and tolerability of IMO-8400 in patients with Waldenstrom's Macroglobulinemia: Assessment of adverse events
Time frame: Up to 24 weeks
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMO-8400 0.6 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 Grade >=3 TEAE | 1 Participants |
| IMO-8400 0.6 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 DLT | 0 Participants |
| IMO-8400 0.6 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 TEAE Leading to Premature Treatment DC | 0 Participants |
| IMO-8400 0.6 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 TEAE Leading to Death | 0 Participants |
| IMO-8400 0.6 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 SAE | 0 Participants |
| IMO-8400 0.6 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 Related TEAE | 5 Participants |
| IMO-8400 0.6 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 TEAE | 6 Participants |
| IMO-8400 1.2 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 TEAE Leading to Death | 0 Participants |
| IMO-8400 1.2 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 TEAE Leading to Premature Treatment DC | 0 Participants |
| IMO-8400 1.2 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 Related TEAE | 2 Participants |
| IMO-8400 1.2 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 DLT | 0 Participants |
| IMO-8400 1.2 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 TEAE | 5 Participants |
| IMO-8400 1.2 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 Grade >=3 TEAE | 2 Participants |
| IMO-8400 1.2 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 SAE | 0 Participants |
| IMO-8400 1.2 mg/kg 2x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 TEAE Leading to Premature Treatment DC | 4 Participants |
| IMO-8400 1.2 mg/kg 2x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 TEAE | 14 Participants |
| IMO-8400 1.2 mg/kg 2x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 TEAE Leading to Death | 0 Participants |
| IMO-8400 1.2 mg/kg 2x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 Grade >=3 TEAE | 7 Participants |
| IMO-8400 1.2 mg/kg 2x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 Related TEAE | 12 Participants |
| IMO-8400 1.2 mg/kg 2x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 DLT | 1 Participants |
| IMO-8400 1.2 mg/kg 2x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 SAE | 1 Participants |
| IMO-8400 2.4 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 TEAE Leading to Premature Treatment DC | 2 Participants |
| IMO-8400 2.4 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 Related TEAE | 6 Participants |
| IMO-8400 2.4 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 SAE | 2 Participants |
| IMO-8400 2.4 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 DLT | 0 Participants |
| IMO-8400 2.4 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 Grade >=3 TEAE | 3 Participants |
| IMO-8400 2.4 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 TEAE Leading to Death | 0 Participants |
| IMO-8400 2.4 mg/kg 1x/wk | Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | At Least 1 TEAE | 6 Participants |
Secondary
Best Overall Response
Best Overall Response using criteria from the VIth International Workshop in Waldenstrom's Macroglobulinemia
Time frame: Up to 24 weeks
Population: Efficacy Evaluable Population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMO-8400 0.6 mg/kg 1x/wk | Best Overall Response | Not Evaluable | 0 Participants |
| IMO-8400 0.6 mg/kg 1x/wk | Best Overall Response | Very Good Partial Response | 0 Participants |
| IMO-8400 0.6 mg/kg 1x/wk | Best Overall Response | Complete Response | 0 Participants |
| IMO-8400 0.6 mg/kg 1x/wk | Best Overall Response | Minor Response | 2 Participants |
| IMO-8400 0.6 mg/kg 1x/wk | Best Overall Response | Standard Deviation | 2 Participants |
| IMO-8400 0.6 mg/kg 1x/wk | Best Overall Response | Partial Response | 1 Participants |
| IMO-8400 0.6 mg/kg 1x/wk | Best Overall Response | Progressive Disease | 0 Participants |
| IMO-8400 1.2 mg/kg 1x/wk | Best Overall Response | Partial Response | 0 Participants |
| IMO-8400 1.2 mg/kg 1x/wk | Best Overall Response | Standard Deviation | 3 Participants |
| IMO-8400 1.2 mg/kg 1x/wk | Best Overall Response | Complete Response | 0 Participants |
| IMO-8400 1.2 mg/kg 1x/wk | Best Overall Response | Not Evaluable | 0 Participants |
| IMO-8400 1.2 mg/kg 1x/wk | Best Overall Response | Very Good Partial Response | 0 Participants |
| IMO-8400 1.2 mg/kg 1x/wk | Best Overall Response | Progressive Disease | 1 Participants |
| IMO-8400 1.2 mg/kg 1x/wk | Best Overall Response | Minor Response | 0 Participants |
| IMO-8400 1.2 mg/kg 2x/wk | Best Overall Response | Minor Response | 4 Participants |
| IMO-8400 1.2 mg/kg 2x/wk | Best Overall Response | Partial Response | 2 Participants |
| IMO-8400 1.2 mg/kg 2x/wk | Best Overall Response | Complete Response | 0 Participants |
| IMO-8400 1.2 mg/kg 2x/wk | Best Overall Response | Very Good Partial Response | 0 Participants |
| IMO-8400 1.2 mg/kg 2x/wk | Best Overall Response | Standard Deviation | 4 Participants |
| IMO-8400 1.2 mg/kg 2x/wk | Best Overall Response | Progressive Disease | 1 Participants |
| IMO-8400 1.2 mg/kg 2x/wk | Best Overall Response | Not Evaluable | 1 Participants |
| IMO-8400 2.4 mg/kg 1x/wk | Best Overall Response | Very Good Partial Response | 0 Participants |
| IMO-8400 2.4 mg/kg 1x/wk | Best Overall Response | Not Evaluable | 0 Participants |
| IMO-8400 2.4 mg/kg 1x/wk | Best Overall Response | Progressive Disease | 1 Participants |
| IMO-8400 2.4 mg/kg 1x/wk | Best Overall Response | Complete Response | 0 Participants |
| IMO-8400 2.4 mg/kg 1x/wk | Best Overall Response | Partial Response | 0 Participants |
| IMO-8400 2.4 mg/kg 1x/wk | Best Overall Response | Standard Deviation | 3 Participants |
| IMO-8400 2.4 mg/kg 1x/wk | Best Overall Response | Minor Response | 1 Participants |
Secondary
Identify the Number of Patients Experiencing DLTs at Each Dose Level
To identify an appropriate dose of IMO-8400 for further clinical evaluation via evaluation of DLT at each dose level
Time frame: 28 days
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMO-8400 0.6 mg/kg 1x/wk | Identify the Number of Patients Experiencing DLTs at Each Dose Level | 0 Participants |
| IMO-8400 1.2 mg/kg 1x/wk | Identify the Number of Patients Experiencing DLTs at Each Dose Level | 0 Participants |
| IMO-8400 1.2 mg/kg 2x/wk | Identify the Number of Patients Experiencing DLTs at Each Dose Level | 1 Participants |
| IMO-8400 2.4 mg/kg 1x/wk | Identify the Number of Patients Experiencing DLTs at Each Dose Level | 0 Participants |
Secondary
Pharmacokinetics of Escalating Dose Levels of IMO 8400 Administered by SC Injection - AUC0-t (hr*ng/mL)
Pharmacokinetics of escalating dose levels of IMO 8400 administered by SC injection - AUC0-t (hr\*ng/mL) .
Time frame: Cycle 1 Week 1 Day 1: Samples were obtained pre-dose (within 1 hr prior to injection) and post-dose at 1 hr (+/-5 min), 2 hrs (+/-10 min) and 4 hrs (+/-15 min)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| IMO-8400 0.6 mg/kg 1x/wk | Pharmacokinetics of Escalating Dose Levels of IMO 8400 Administered by SC Injection - AUC0-t (hr*ng/mL) | 2565.8 AUC0-t (hr*ng/mL) | Geometric Coefficient of Variation 64.6 |
| IMO-8400 1.2 mg/kg 1x/wk | Pharmacokinetics of Escalating Dose Levels of IMO 8400 Administered by SC Injection - AUC0-t (hr*ng/mL) | 6493.0 AUC0-t (hr*ng/mL) | Geometric Coefficient of Variation 61.7 |
| IMO-8400 1.2 mg/kg 2x/wk | Pharmacokinetics of Escalating Dose Levels of IMO 8400 Administered by SC Injection - AUC0-t (hr*ng/mL) | 7229.3 AUC0-t (hr*ng/mL) | Geometric Coefficient of Variation 54.5 |
| IMO-8400 2.4 mg/kg 1x/wk | Pharmacokinetics of Escalating Dose Levels of IMO 8400 Administered by SC Injection - AUC0-t (hr*ng/mL) | 13691.7 AUC0-t (hr*ng/mL) | Geometric Coefficient of Variation 32.3 |
Secondary
Pharmacokinetics of Escalating Dose Levels of IMO 8400 Administered by SC Injection - Cmax.
Pharmacokinetics of escalating dose levels of IMO 8400 administered by SC injection - Cmax.
Time frame: Cycle 1 Week 1 Day 1: Samples were obtained pre-dose (within 1 hr prior to injection) and post-dose at 1 hr (+/-5 min), 2 hrs (+/-10 min) and 4 hrs (+/-15 min)
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| IMO-8400 0.6 mg/kg 1x/wk | Pharmacokinetics of Escalating Dose Levels of IMO 8400 Administered by SC Injection - Cmax. | 807.6 Cmax (ng/mL) | Geometric Coefficient of Variation 70.3 |
| IMO-8400 1.2 mg/kg 1x/wk | Pharmacokinetics of Escalating Dose Levels of IMO 8400 Administered by SC Injection - Cmax. | 2137.9 Cmax (ng/mL) | Geometric Coefficient of Variation 68.7 |
| IMO-8400 1.2 mg/kg 2x/wk | Pharmacokinetics of Escalating Dose Levels of IMO 8400 Administered by SC Injection - Cmax. | 2421.2 Cmax (ng/mL) | Geometric Coefficient of Variation 50.8 |
| IMO-8400 2.4 mg/kg 1x/wk | Pharmacokinetics of Escalating Dose Levels of IMO 8400 Administered by SC Injection - Cmax. | 4433.1 Cmax (ng/mL) | Geometric Coefficient of Variation 29.9 |