Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Imetelstat · 16 trials · 20 indications
Overall survival is defined as the time interval from randomization date to date of death from any cause.
The combined response assessment criteria for MDS and AML based on IWG (International Working Group) 2018 criteria (MDS) and the criteria of the European LeukemiaNet (AML) will be used to define responders. The response rate is calculated as number of responders divided by the number of all participants of the analysis set.
Percentage of participants without any RBC transfusion during any consecutive 8 weeks (56 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2. The 95% confidence interval (CI) was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place.
Percentage of participants without any RBC transfusion during any consecutive 8 weeks (56 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2. The 95% confidence interval (CI) was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place.
Percentage of participants without any RBC transfusion during any consecutive 8 weeks (56 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2. The 95% CI was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place.
Spleen response rate is defined as the percentage of participants who achieved ≥ 35% reduction in spleen volume at Week 24 from baseline performed by the IRC using magnetic resonance imaging (MRI).
Symptom response rate is defined as percentage of participants who achieved ≥ 50% reduction in total symptom score (TSS) at Week 24 from baseline as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) version 2.0 diary. The MFSAF assessed following symptoms due to Myelofibrosis (MF): night sweats, itchiness, abdominal discomfort, pain under ribs on left side, feeling of fullness, bone or muscle pain and degree of inactivity. Each item is scored on a scale of 0 (absent) to 10 (worst imaginable) with higher scores indicating more severe symptoms and greater inactivity. The total score ranges from 0-70, where 0 indicates absent/as good as it can be and 70 indicates worst imaginable/as bad as it can be.
OR:CI/PR/CR per IWG-MRT. CR:Bone marrow (BM):\<5% blasts;≤Grade 1 MF, AND Peripheral blood:Hemoglobin (Hb) ≥100 g/liter (g/L) and \<upper normal limit (UNL);Neutrophil count(NC) ≥1x10\^9/L and \<UNL; Platelet(PLT) count ≥100x10\^9/L and \<UNL;\<2% immature myeloid cells(IMCs), AND Clinical: Resolution of disease symptoms; Spleen and liver not palpable; No evidence of extramedullary hematopoeisis(EMH). PR:All CR criteria plus peripheral blood: Hb≥85 but \<100g/L and \<UNL; NC ≥1x10\^9/L and \<UNL; PLT count ≥50 but \<100x10\^9/L and \<UNL;\<2%IMCs. CI:achievement of anemia (≥20 g/L increase in Hb level), spleen(baseline splenomegaly palpable at 5-10 cm, below left costal margin(LCM), becomes not palpable), symptoms response (50% reduction in total symptom score) without progressive disease (PD) (appearance of new splenomegaly- palpable at least \[≥\]5 cm below LCM)/increase in severity of anemia, thrombocytopenia/neutropenia. Data is reported separately for arms whose response was assessed per IWG-MRT.
For this pilot study, overall response was defined as achievement of a leukemic response (i.e. a clinically meaningful reduction in Blast cells). This was quantified as \<5% peripheral blood and bone marrow blasts % that lasts for at least two months. Data is reported separately for this arm where response was assessed by this specific criterion.
OR: HI/PR/CR per IWG. CR: BM:≤5% myeloblasts (all cell lines normal maturation), Peripheral blood:Hgb ≥11g/dL, PLTs ≥100x10\^9/L, Neutrophils ≥1.0x10\^9/L, Blasts 0%. PR: All CR criteria if abnormal before treatment except- BM blasts decreased ≥50% over pretreatment but still \>5%, Cellularity, morphology not relevant. HI responses:1) Erythroid: Hgb increase ≥1.5 g/dL, Relevant reduction of red blood cell(RBC) units transfusions by absolute ≥4 RBC transfusions/8 week (wk) compared with pretreatment transfusion number in previous 8 wk. Only RBC transfusions given for Hgb of ≤9.0 g/dL.2)PLTs:Absolute increase ≥30x10\^9/L starting \>20x10\^9/L PLTs; Increase from \<20x10\^9/L to \>20x10\^9/L and by ≥100%; 3)Neutrophil: ≥100% increase, absolute increase \>0.5x10\^9/L; 4)Progression/relapse after HI:≥1 of following:≥50% decrement from maximum response levels in granulocytes/PLTs, Reduction in Hgb ≥1.5 g/dL,Transfusion dependence. Data is reported separately for arm whose response was assessed per IWG.
Primary objectives are as follows: ET patients - best hematologic response within the first year of therapy and PV patients - maintenance of Hct \< 45% in men and \< 42% in women (or pre-specified Hct count that is tolerable) without phlebotomy or myelosuppressive therapy within the first year of therapy. Secondary objectives, to determine the durability of hematologic response and to determine the rate of phlebotomy required within the first year of therapy.
To determine the rate of improvement in response in patients with previously treated multiple myeloma following treatment with imetelstat alone or in combination wtih lenalidomide maintenance therapy. Response will be assessed using the International Uniform Response Criteria for Multiple Myeloma (IURCMM).
Defined as the time from randomization to documented disease progression, as determined by the investigator's assessment according to RECIST, or death from any cause, whichever occurs first.
The DLT-evaluable population includes participants in the Part A portion of the trial who received at least one dose of imetelstat and azacitidine and either experienced a Dose-Limiting Toxicity (DLT) during the first-cycle DLT assessment period or completed their first-cycle DLT assessment.
Frequency percent (%) of patients with acute myeloid leukemia (AML) in second or greater relapse or refractory to relapse therapy who experience a cycle 1 dose limiting toxicity to imetelstat administered in combination with fludarabine and cytarabine stratified by dose level.
Safety will be assessed based on incidence and severity (according to Common Terminology Criteria for Adverse Events) of treatment emergent adverse events from the first dose of study treatment until 30 days after completion of treatment.
Symptom response rate is defined as percentage of participants with \>=50% reduction in the Total Symptom Score (TSS) measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 e-diary at 24 week compared to baseline.
| Arm | Type | Description |
|---|---|---|
| Imetelstat | EXPERIMENTAL | Participants will receive imetelstat sodium at 9.4 mg/kg intravenous (IV) every 21 days (±3 days), until disease progression or unacceptable toxicity, treatment discontinuation or study end. |
| Best Available Therapy (BAT) | ACTIVE_COMPARATOR | Participants will receive BAT (investigator-selected non-JAK-inhibitor treatment), until disease progression or unacceptable toxicity, treatment discontinuation or study end. Participants on BAT who meet protocol-defined criteria for progressive disease may crossover to receive imetelstat treatment after sponsor's approval. |
| Single-arm imetelstat | EXPERIMENTAL | - |
| Phase 2: Imetelstat Sodium | EXPERIMENTAL | Imetelstat sodium administered intravenously (IV), at a starting dose of 7.5 milligrams per kilogram (mg/kg), every 4 weeks (on a 28-day cycle) until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first. Dose escalation to 9.4 mg/kg was allowed before Protocol Amendment 2. |
| Phase 3: Imetelstat Sodium | EXPERIMENTAL | Imetelstat sodium administered IV, at a starting dose of 7.5 mg/kg, every 4 weeks (on a 28-day cycle) until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first. |
| Phase 3: Placebo | PLACEBO_COMPARATOR | Imetelstat sodium-matching placebo administered IV, every 4 weeks (on a 28-day cycle), until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first. |
| QTc Substudy: Imetelstat Sodium | EXPERIMENTAL | Imetelstat sodium administered IV, at a starting dose of 7.5 mg/kg, every 4 weeks (on a 28-day cycle) until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first. |
| QTc Substudy: Placebo | PLACEBO_COMPARATOR | Imetelstat sodium-matching placebo administered IV, every 4 weeks (on a 28-day cycle), until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first. If after a minimum of 2 treatment cycles a participant has no significant change to pRBC transfusion burden or evidence of clinical benefit per Investigator, after discussion with the Sponsor the participant, he/she may be permitted to start treatment with imetelstat sodium. |
| Extension Phase: Imetelstat Sodium | EXPERIMENTAL | Participants randomized to the imetelstat sodium arm in the Phase 3 and the VR QTc Substudy, based on the response will continue to receive imetelstat sodium IV, at the dose they were receiving in the Phase 3 or VR QTc Substudy, every 4 weeks (on a 28-day cycle) until death, lost to follow-up, withdrawal of consent, study termination, or up to 3 years whichever occurs first. |
| Extension Phase: Extended Follow-up | EXPERIMENTAL | Participants randomized to the placebo arm in the Phase 3 study will enter the Extended Follow-up part of the Extension Phase and continue in follow up until death, lost to follow-up, withdrawal of consent, study termination, or whichever occurs first up to approximately 3 years. |
| Imetelstat 4.7 mg/kg | EXPERIMENTAL | - |
| Imetelstat 9.4 mg/kg | EXPERIMENTAL | - |
| Arm A: Imetelstat 9.4 mg/kg (Myelofibrosis [MF]) | EXPERIMENTAL | Participants with MF regardless of spliceosome mutation status or presence of ring sideroblasts received imetelstat 9.4 milligram per kilogram (mg/kg), intravenously (IV) as 2-hour infusion on Day 1 of each 21-day cycle in Core Phase up to 9 cycles. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). |
| Arm B: Imetelstat 9.4 mg/kg as Induction + Maintenance (MF) | EXPERIMENTAL | Participants with MF regardless of spliceosome mutation status or presence of ring sideroblasts received imetelstat 9.4 mg/kg, IV as 2-hour infusion on Days 1, 8, and 15 of 21-day cycle in Cycle 1 followed by 9.4 mg/kg on Day 1 of each 21-day cycle up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). |
| Arm D: Imetelstat 9.4 mg/kg (Blast-phase MF/Acute Myeloid Leukemia) | EXPERIMENTAL | Participants with blast-phase myelofibrosis/acute myeloid leukemia (MF/AML) received imetelstat 9.4 mg/kg, IV as 2-hour infusion weekly on Days 1, 8, 15, 22 of a 28-day cycle up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). |
| Arm E: Imetelstat 7.5 - 9.4 mg/kg (MF [with Spliceosome Mutation or Ring Sideroblasts]) | EXPERIMENTAL | Participants with MF and spliceosome mutations or ring sideroblasts present received 2 cycles (Cycles 1-2) of imetelstat 7.5 mg/kg, IV as 2-hour infusion on Day 1 of a 28-day cycle followed by maintenance therapy with the same regimen or the possibility of dose escalation to imetelstat 9.4 mg/kg weekly if response to the initial dose was insufficient up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). |
| Arm F: Imetelstat 7.5 - 9.4 mg/kg (MF [without spliceosome mutation and ring sideroblasts]) | EXPERIMENTAL | Participants with MF without spliceosome mutations or ring sideroblasts present received 2 cycles (Cycles 1-2) of imetelstat 9.4 mg/kg, IV as 2-hour infusion on Day 1 of a 28-day cycle followed by maintenance therapy with the same regimen or imetelstat 7.5 mg/kg twice weekly on Days 1, 3 for 2 cycles of 28-day cycle (Cycles 3-4) followed by imetelstat 7.5 mg/kg 3-times-weekly on Days 1, 3, 5 of Cycles 5 and beyond of 28-day cycle up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). |
| Arm G: Imetelstat 7.5 - 9.4 mg/kg (MDS/MPN or MDS with Spliceosome Mutations or Ring Sideroblasts) | EXPERIMENTAL | Participants with either myelodysplastic syndromes/ myeloproliferative neoplasm (MDS/MPN) or MDS and spliceosome mutations or ring sideroblasts present received 2 cycles of 28-day cycle (Cycles 1-2) of imetelstat 7.5 mg/kg, IV as 2-hour infusion on Day 1 of a 28-day cycle followed by maintenance therapy with the same regimen or the possibility of dose escalation to imetelstat 9.4 mg/kg weekly if response to the initial dose was insufficient up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). |
| Imetelstat (7.5 mg/kg) | EXPERIMENTAL | Imetelstat (7.5 mg/kg) with or without lenalidomide standard of care |
| Imetelstat (9.4 mg/kg) | EXPERIMENTAL | Imetelstat (9.4 mg/kg) with or without lenalidomide standard of care |
| Imetelstat + Paclitaxel (with or without bevacizumab) | EXPERIMENTAL | - |
| Paclitaxel (with or without bevacizumab) alone | EXPERIMENTAL | - |
| imetelstat plus standard of care | EXPERIMENTAL | imetelstat plus standard of care (bevacizumab or observation) |
| Standard of care | OTHER | Bevacizumab or observation |
| Part A Safety Run-In phase: Imetelstat in combination with Azacitidine | ACTIVE_COMPARATOR | Part A combination therapy: * Imetelstat will be administered on Day 1 of each 28-day cycle * Azacitidine once daily for Days 1 (+/- 1 day) through 7 (+/- 1 day) of each 28-day cycle. |
| Part B Combination Therapy: Imetelstat in combination with Azacitidine with or without Venetoclax | ACTIVE_COMPARATOR | * Imetelstat will be administered on Day 1 of each 28-day cycle * Azacitidine once daily for Days 1 (+/- 1 day) through 7 (+/- 1 day) of each 28-day cycle. * Venetoclax once daily for Days 1 (+/- 1 day) through 14 (+/- 1 day) of each 28-day cycle. |
| Treatment (Imetelstat, fludarabine, cytarabine) | EXPERIMENTAL | Patients receive imetelstat IV over 2 hours on days 1 and 8, fludarabine IV over 1 hour on days 2-6, and cytarabine IV over 1-3 hours on days 2-6 of each cycle. Patients also receive cytarabine IT alone or with methotrexate IT, and hydrocortisone IT at the provider's discretion. Patients may also receive leucovorin calcium IV or PO 24 and 30 hours after each IT triples dose. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, bone marrow biopsy and/or aspiration, blood sample collection, and lumbar puncture for CSF sample collection during screening and on the trial. |
| Part 1: Imetelstat sodium + Ruxolitinib | EXPERIMENTAL | Participants who have received ruxolitinib orally (PO) as part of standard of care (SOC) for at least 12 weeks prior to Screening will be enrolled. After enrollment, participants will initiate imetelstat sodium therapy. Dose levels of imetelstat sodium may include 4.7, 6, 7.5, 9.4 mg/kg, until a RP2D is established. |
| Part 2: Imetelstat sodium + Ruxolitinib | EXPERIMENTAL | Cohort A: Janus Kinase (JAK) inhibitor naive participants will receive initial treatment with ruxolitinib on study for at least 12 weeks, including 4 consecutive weeks at a stable dose, prior to the addition of imetelstat sodium. Participants can begin imetelstat sodium treatment after sponsor review and approval and meet the following requirements: platelet value is ≥75 x 10\^9/L for two consecutive measurements, at least 1 week apart, and the participant does not meet criteria for dose delay. Note that the study will no longer recruit participants into Cohort A. Cohort B: Participants will receive treatment with ruxolitinib for 12 weeks with at least 4 consecutive weeks at a stable dose prior to enrollment and will start combination treatment with imetelstat on study. |
| 1 | EXPERIMENTAL | 3+3 cohort dose escalation |
| Single Arm Trial | EXPERIMENTAL | Patients will be enrolled in the order of confirmation of eligibility. Dose cohorts will be filled sequentially with a minimum of 3 patients. Once assigned to a dose cohort, each patient will continue to be treated at the same dose level throughout the course of the study. |
| Dose escalation | EXPERIMENTAL | Treatment Schedule 3 will consist of dosing on Days 1, 4, 8, and 11 of each 21 day cycle (3 weeks equals 1 cycle) and Treatment Schedule 4 will consist of dosing on Day 1 of each 28 day cycle (4 weeks equals 1 cycle) |
| Name | Type | Description |
|---|---|---|
| Imetelstat | DRUG | Imetelstat sodium will be given intravenously at 9.4 mg/kg every 21 days, until disease progression or unacceptable toxicity, treatment discontinuation or study end. |
| Best Available Therapy (BAT) | DRUG | Non-JAK-inhibitor treatment will be given, which may include but is not limited to hydroxyurea, thalidomide or an analog of thalidomide, interferon, danazol, hypomethylating agents, chemotherapy or radiotherapy. |
| Imetelstat sodium | DRUG | Intravenous injection |
| Placebo | DRUG | Imetelstat sodium-matching placebo IV infusion. |
| Imetelstat 4.7 mg/kg | DRUG | Participants received imetelstat 4.7 mg/kg of body weight as intravenous infusion on Day 1 of each 21-day cycle. Study drug was administered intravenously until disease progression, unacceptable toxicity, or study end. |
| Imetelstat 9.4 mg/kg | DRUG | Participants received imetelstat 9.4 mg/kg of body weight as intravenous infusion on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or study end. |
| Imetelstat (7.5 mg/kg) | DRUG | Imetelstat 7.5 mg/kg as a 2-hour intravenous infusion (± 10 minutes) on Days 1 and 8 of a 28-day cycle; the Day 8 dose will be omitted in patients with a prior history of bone marrow or stem cell transplant. |
| lenalidomide standard of care | DRUG | Patients who are receiving lenalidomide as maintenance therapy upon enrollment as part of their treatment regimen may remain on this therapy during trial participation, provided that they have received this treatment for a minimum of 3 months and demonstrate evidence of stabilization of their response. |
| Imetelstat (9.4 mg/kg) | DRUG | Imetelstat 9.4 mg/kg as a 2-hour intravenous infusion (± 10 minutes) on Days 1 and 8 of a 28-day cycle; the Day 8 dose will be omitted in patients with a prior history of bone marrow or stem cell transplant. |
| Bevacizumab | DRUG | Bevacizumab is administered at 15 mg/kg on day one of a 21 day cycle |
| Paclitaxel | DRUG | Paclitaxel is administered at 90 mg/m2 on days one and eight of a 21 day cycle |
| Azacitidine | DRUG | 75mg/m2 IV or subcutaneous (SQ) once daily for Days 1 (+/- 1 day) through 7 (+/- 1 day) of each 28-day cycle. Azacitidine can be administered locally as long as documentation of administration is provided to the study team. |
| Venetoclax | DRUG | Venetoclax 400mg oral once daily for Days 1 (+/- 1 day) through 14 (+/- 1 day) of each 28-day cycle. Venetoclax reduced dosey should be substituted if concomitant posaconazole, or if other concomitant strong CYP3A4 inhibitor (e.g. voriconazole) or 200mg for moderate CYP3A4 inhibitor (e.g. isavuconazole). For Cycle 1, participants will receive a venetoclax ramp-up dose on day 1, day 2, and days 3-14 of venetoclax,. If the participant is being treated with concomitant posaconazole, or other concomitant strong CYP3A4 inhibitor, or with a concomitant moderate CYP3A4 inhibitor or a pg-p inhibitor, participants will receive a lower ramp-up dose on day 1, day 2, and days 3-14 of venetoclax. |
| Biospecimen Collection | PROCEDURE | Undergo blood and CSF sample collection |
| Bone Marrow Aspiration | PROCEDURE | Undergo bone marrow biopsy and aspiration |
| Bone Marrow Biopsy | PROCEDURE | Undergo bone marrow biopsy and aspiration |
| Cytarabine | DRUG | Given IV and IT |
| Echocardiography Test | PROCEDURE | Undergo ECHO |
| Fludarabine | DRUG | Given IV |
| Hydrocortisone Sodium Succinate | DRUG | Given IT |
| Leucovorin Calcium | DRUG | Given IV or PO |
| Lumbar Puncture | PROCEDURE | Undergo lumbar puncture |
| Methotrexate | DRUG | Given IT |
| Ruxolitinib | DRUG | Ruxolitinib will be administered, orally (PO), twice daily (BID) in cohort B as the standard of care per local prescribing guidelines. |
| Imetelstat Sodium (GRN163L) | DRUG | 25% dose escalation infused over 2 hours weekly |
Inclusion Criteria: * Diagnosis of primary myelofibrosis according to the revised World Health Organization criteria or post-essential thrombocythemia-MF or post-polycythemia vera-MF according to the IWG-MRT criteria * Dynamic International Prognostic Scoring System intermediate-2 or high-risk MF *...