Multiple Myeloma
Conditions
Brief summary
The purpose of this study is to test the safety and efficacy of the study drug daratumumab, when given together with Pomalidomide, Dexamethasone, and All-Transretinoic Acid (ATRA).
Detailed description
This is a multi-institution phase II study of ATRA in combination with fixed dose Daratumumab, Pomalidomide and Dex for a total of 33 patients in patients with relapsed multiple myeloma who have progressed on the combination of Dara + Len + Dex. There will also be an exploratory cohort with an additional 10 patients who have progressed on the combination of Dara + Pom + Dex.
Interventions
DRUGDaratumumab
During 28-day treatment cycles, patients will receive Dara 16 mg/kg intravenously (IV) at their current dose upon enrollment onto the study depending on their cycle. They will receive Dara depending on the cycle they are in. If they are on cycles 1-2 then they will receive Dara 16 mg/kg IV on days 1,8,15,22; if they are on cycles 3-6 they will receive Dara 16 mg/kg on days 1 and 15; and if they are on cycle 7 or beyond they will receive Dara 16 mg/kg on day 1.
DRUGPomalidomide
Pomalidomide will be administered at the patient's currently tolerated dose (4,3, or 2 mg po daily) on days 1-21
DRUGAll-trans retinoic acid
ATRA will be administered in a divided dose of twice daily as an oral formulation at 45mg/m2/day for 3 days. The first administration of ATRA will be given in the morning, two days before the scheduled Dara infusion. The last administration of ATRA will be given in the evening of the day that Dara was administered
DRUGDexamethasone
Dexamethasone will be administered at 40 mg once weekly on days 1,8,15 for patients 75 years old and younger and at 20 mg once weekly on days 1,8,15 for patients older than 75.
Sponsors
Janssen, LP
Hackensack Meridian Health
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Documented multiple myeloma 2. For cohort A, patients must have been previously exposed to Dara+Len+Dex and must have achieved at least stable disease to this combination. 3. For cohort B, patients must have been exposed to Dara + Pom + Dex and must have achieved at least stable disease to this combination. 4. Histologically confirmed and relapsed multiple myeloma with measurable disease, defined by at least one of the following: 1. Serum monoclonal protein ≥0.5 g/dL; 2. Monoclonal protein in the urine on 24-hour electrophoresis ≥200 mg; 3. Serum immunoglobulin free light chain (FLC) ≥10 mg/dL (100 mg/L) provided serum FLC ratio is abnormal; 4. New of progressing biopsy proven plasmacytoma on exam or imaging; or 5. Bone marrow plasma cells ≥20%; 5. Cycle 1 day 1 of study treatment must be within 3 months of last exposure to Daratumumab. 6. Life expectancy \>3 months 7. ECOG PS 0-2 8. Age ≥18 9. Adequate organ function, including bone marrow, renal, hepatic, pulmonary, and cardiac function based on the last assessment performed within the Screening Period, defined as: 1. Absolute neutrophil count (ANC) ≥1,000/μL; 2. Platelet count ≥50,000/μL, (≥30,000/μL if bone marrow plasma cells are ≥50% of cellularity); 3. Hemoglobin ≥7.5g/dL; 4. Creatinine clearance ≥60 mL/min (assessed as glomerular filtration rate using the Cockcroft-Gault formula); 5. Alanine aminotransferase or aspartate aminotransferase \<3 x upper limit of normal (ULN); 6. Total bilirubin \<2 x ULN (except for patients with Gilbert's syndrome confirmed by UGT1A1 mutation); 7. Left ventricular ejection fraction ≥50% as assessed by echocardiography or multi-gated acquisition (MUGA) scan; and 8. Must have a minimum level of pulmonary reserve defined as Grade \<2 dyspnea and pulse oxygenation ≥92% on room air; 10. Prior to first dose of study drug, a woman must be either: * Not of childbearing potential: premenarchal; postmenopausal (\>45 years of age with amenorrhea for at least 12 months or any age with amenorrhea for at least 6 months and a serum follicle stimulating hormone level \>40 IU/L or mIU/mL\]); permanently sterilized (eg, bilateral tubal occlusion \[which includes tubal ligation procedures as consistent with local regulations\], hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or otherwise be incapable of pregnancy * Of childbearing potential and practicing a highly effective method of birth control for 4 weeks before initiating study treatment that is consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies: e.g., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device or intrauterine system; barrier methods: condom with spermicidal foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; male partner sterilization (the vasectomized partner should be the sole partner for that subject); true abstinence (when this is in line with the preferred and usual lifestyle of the subject) Note: If the childbearing potential changes after start of the study (e.g., woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) * a woman must begin a highly effective method of birth control, as described above. 11. A woman of childbearing potential must have 2 negative serum (β human chorionic gonadotropin) or urine pregnancy tests during screening, the first one within 28 days prior to the first dose of study drug and the second within 24 hours prior to the first dose of study drug. 12. A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control e.g., either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the study and for 3 months after receiving the last dose of study drug. 13. Subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol and referenced in the informed consent form (ICF).
Exclusion criteria
1. Major concurrent illness or organ dysfunction 2. Active GVHD requiring systemic corticosteroids in a subject who previously received allogeneic-SCT. 3. Cord compression or CNS involvement 4. Recent/Prior active malignancy requiring active therapy 2 years prior to enrollment excluding non-melanoma skin cancer. 5. Prior life-threatening hypersensitivity to daratumumab or an IMiD 6. Plasma cell leukemia 7. Pregnant or lactating females 8. Men donating sperm during study 9. Seropositive for human immunodeficiency virus (HIV) 10. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen \[HBsAg\]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen \[anti-HBc\] and/or antibodies to hepatitis B surface antigen \[anti-HBs\]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR 11. Seropositive for hepatitis C (except in the setting of a sustained virologic response \[SVR\], defined as aviremia at least 12 weeks after completion of antiviral therapy) 12. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) less than 50% of predicted normal
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (Cohort A) | 12 Months | To determine the ORR of the combination of Dara + Pom + Dex + ATRA in patients progressing on Dara + Len + Dex (Cohort A) |
| Incidence of Adverse Events | 12 Months | Incidence of Adverse Events in the combination of Dara + Pom + Dex + ATRA using CTCAE V5 criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events | 12 Months | To define the toxicity using CTCAE V5 criteria. |
| Rate of Minimal Residual Disease Evaluation | 12 Months | To evaluate the status of minimal residual disease (MRD) in patients who achieve sCR, CR, or nCR. |
| Time on Study (TOS) | 12 Months | Duration from start of study treatment to end of study |
| Objective Response Rate (Cohort B) | 12 Months | To determine the ORR of the combination of Dara + Pom + Dex + ATRA in patients progressing on Dara + Pom + Dex |
| Time To Progression (TTP) | 12 Months | Duration from start of study treatment to progression |
| Progression-Free Survival (PFS) | 12 Months | Duration from start of study treatment to PD or death \[regardless of cause\], whichever comes first |
| Overall Survival (OS) | 12 Months | Duration from start of study treatment to death |
| Duration of Response (DOR) | 12 Months | Duration from treatment response to progression |
| Rate of Stringent Complete Response | 12 Months | To determine the best stringent complete response (sCR)/CR/near CR (nCR) and \>/= very good partial response (VGPR) rates. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Progressed on Daratumumab + Lenalidomide + Dexamethasone (Cohort A) Patients with relapsed or refractory multiple myeloma who have progressed on the combination of Dara + Len + Dex (Cohort A) to be treated with a combination of Dara + Pom + Dex + ATRA (All-Transretinoic Acid)
Daratumumab: During 28-day treatment cycles, patients will receive Dara 16 mg/kg intravenously (IV) at their current dose upon enrollment onto the study depending on their cycle. They will receive Dara depending on the cycle they are in. If they are on cycles 1-2 then they will receive Dara 16 mg/kg IV on days 1,8,15,22; if they are on cycles 3-6 they will receive Dara 16 mg/kg on days 1 and 15; and if they are on cycle 7 or beyond they will receive Dara 16 mg/kg on day 1.
Pomalidomide: Pomalidomide will be administered at the patient's currently tolerated dose (4,3, or 2 mg po daily) on days 1-21
All-trans retinoic acid: ATRA will be administered in a divided dose of twice daily as an oral formulation at 45mg/m2/day for 3 days. The first administration of ATRA will be given in the morning, two days before the scheduled Dara infusion. The last administration of ATRA will be given in the evening of the day that Dara was administered
Dexamethasone: Dexamethasone will be administered at 40 mg once weekly on days 1,8,15 for patients 75 years old and younger and at 20 mg once weekly on days 1,8,15 for patients older than 75. | 1 |
| Progressed on Daratumumab + Pomalidomide + Dexamethasone (Cohort B) Patients with relapsed or refractory multiple myeloma who have progressed on the combination of Dara + Pom + Dex (Cohort B) to be treated with a combination of Dara + Pom + Dex + ATRA (All-Transretinoic Acid)
Daratumumab: During 28-day treatment cycles, patients will receive Dara 16 mg/kg intravenously (IV) at their current dose upon enrollment onto the study depending on their cycle. They will receive Dara depending on the cycle they are in. If they are on cycles 1-2 then they will receive Dara 16 mg/kg IV on days 1,8,15,22; if they are on cycles 3-6 they will receive Dara 16 mg/kg on days 1 and 15; and if they are on cycle 7 or beyond they will receive Dara 16 mg/kg on day 1.
Pomalidomide: Pomalidomide will be administered at the patient's currently tolerated dose (4,3, or 2 mg po daily) on days 1-21
All-trans retinoic acid: ATRA will be administered in a divided dose of twice daily as an oral formulation at 45mg/m2/day for 3 days. The first administration of ATRA will be given in the morning, two days before the scheduled Dara infusion. The last administration of ATRA will be given in the evening of the day that Dara was administered
Dexamethasone: Dexamethasone will be administered at 40 mg once weekly on days 1,8,15 for patients 75 years old and younger and at 20 mg once weekly on days 1,8,15 for patients older than 75. | 0 |
| Total | 1 |
Baseline characteristics
| Characteristic | Progressed on Daratumumab + Lenalidomide + Dexamethasone (Cohort A) | Progressed on Daratumumab + Pomalidomide + Dexamethasone (Cohort B) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | — | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | — | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | — | 1 Participants |
| Region of Enrollment United States | 1 participants | — | 1 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 0 |
| other Total, other adverse events | 1 / 1 | 0 / 0 |
| serious Total, serious adverse events | 1 / 1 | 0 / 0 |
Outcome results
Primary
Incidence of Adverse Events
Incidence of Adverse Events in the combination of Dara + Pom + Dex + ATRA using CTCAE V5 criteria.
Time frame: 12 Months
Population: No participants enrolled in cohort B
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Progressed on Daratumumab + Lenalidomide + Dexamethasone (Cohort A) | Incidence of Adverse Events | 1 Participants |
| Progressed on Daratumumab + Pomalidomide + Dexamethasone (Cohort B) | Incidence of Adverse Events | 0 Participants |
Primary
Objective Response Rate (Cohort A)
To determine the ORR of the combination of Dara + Pom + Dex + ATRA in patients progressing on Dara + Len + Dex (Cohort A)
Time frame: 12 Months
Population: No patients enrolled in Cohort B
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Progressed on Daratumumab + Lenalidomide + Dexamethasone (Cohort A) | Objective Response Rate (Cohort A) | 1 Participants |
| Progressed on Daratumumab + Pomalidomide + Dexamethasone (Cohort B) | Objective Response Rate (Cohort A) | 0 Participants |
Secondary
Duration of Response (DOR)
Duration from treatment response to progression
Time frame: 12 Months
Population: No participants enrolled in cohort B
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Progressed on Daratumumab + Lenalidomide + Dexamethasone (Cohort A) | Duration of Response (DOR) | 8 Months |
Secondary
Incidence of Treatment-Emergent Adverse Events
To define the toxicity using CTCAE V5 criteria.
Time frame: 12 Months
Population: No participants enrolled in cohort B
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Progressed on Daratumumab + Lenalidomide + Dexamethasone (Cohort A) | Incidence of Treatment-Emergent Adverse Events | 1 Participants |
| Progressed on Daratumumab + Pomalidomide + Dexamethasone (Cohort B) | Incidence of Treatment-Emergent Adverse Events | 0 Participants |
Secondary
Objective Response Rate (Cohort B)
To determine the ORR of the combination of Dara + Pom + Dex + ATRA in patients progressing on Dara + Pom + Dex
Time frame: 12 Months
Population: No participants enrolled in cohort B
Secondary
Overall Survival (OS)
Duration from start of study treatment to death
Time frame: 12 Months
Population: Patient withdrew consent to follow up at time of progression
Secondary
Progression-Free Survival (PFS)
Duration from start of study treatment to PD or death \[regardless of cause\], whichever comes first
Time frame: 12 Months
Population: No participants enrolled in cohort B
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Progressed on Daratumumab + Lenalidomide + Dexamethasone (Cohort A) | Progression-Free Survival (PFS) | 8 Months |
Secondary
Rate of Minimal Residual Disease Evaluation
To evaluate the status of minimal residual disease (MRD) in patients who achieve sCR, CR, or nCR.
Time frame: 12 Months
Population: No participants enrolled in cohort B
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Progressed on Daratumumab + Lenalidomide + Dexamethasone (Cohort A) | Rate of Minimal Residual Disease Evaluation | 0 Participants |
| Progressed on Daratumumab + Pomalidomide + Dexamethasone (Cohort B) | Rate of Minimal Residual Disease Evaluation | 0 Participants |
Secondary
Rate of Stringent Complete Response
To determine the best stringent complete response (sCR)/CR/near CR (nCR) and \>/= very good partial response (VGPR) rates.
Time frame: 12 Months
Population: No participants enrolled in cohort B
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Progressed on Daratumumab + Lenalidomide + Dexamethasone (Cohort A) | Rate of Stringent Complete Response | 0 Participants |
| Progressed on Daratumumab + Pomalidomide + Dexamethasone (Cohort B) | Rate of Stringent Complete Response | 0 Participants |
Secondary
Time on Study (TOS)
Duration from start of study treatment to end of study
Time frame: 12 Months
Population: Patient withdrew consent to follow up at time of progression. No participants enrolled in cohort B
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Progressed on Daratumumab + Lenalidomide + Dexamethasone (Cohort A) | Time on Study (TOS) | 8 Months |
Secondary
Time To Progression (TTP)
Duration from start of study treatment to progression
Time frame: 12 Months
Population: No participants enrolled in cohort B
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Progressed on Daratumumab + Lenalidomide + Dexamethasone (Cohort A) | Time To Progression (TTP) | 8 Months |