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Also known as Perifosine
perifosine+ temsirolimus · 23 trials · 26 indications
To investigate whether perifosine has a response rate of \> 20% in this group of patients with chemo-insensitive sarcomas.
This is a two-arm Phase II trial to determine whether the experimental regimen is likely to provide a 20% response rate while controlling the toxicity rate at 15%. Response will be evaluated at 2 months from the start of therapy, and is defined using the Choi Criteria. Toxicity is defined as any of the following events: regimen-related death, grade 3 transaminitis, grade 3 gastrointestinal toxicity, or grade 4 fatigue or higher within the same 2-month time window.
To estimate the progression free survival of Multi-Targeted Kinase Inhibitor (TKI) resistant patients with metastatic Renal Cell Carcinoma (RCC) who are treated with perifosine
To determine the response rate (the combined Complete Response (CR) + Partial Response (PR) + Minor Response (MR) following treatment with perifosine in patients with multiple myeloma who have relapsed following Initial front-line therapy and are refractory to their most recent therapy.
All patients included in the study must be assessed for response to treatment, unless there are major protocol treatment deviations or they are ineligible. Even a 5% response rate would be of interest for this agent, given the different nature and mechanism of action of this compound.
Clinical benefit, defined as either an objective response by RECIST or PFS \>12 weeks, is a primary endpoint of the study. The clinical benefit rate together with its two-sided exact binomial 95% confidence interval will be reported.
To determine for each disease category the proportion of patients treated with perifosine who experience a favorable outcome, defined as a complete or partial response; a 50% increase in progression-free survival compared to patient's latest treatment regimen for metastatic disease, or stabilization of disease.
Time to progression will be measured from the first day of study drug until progression.
The frequency of grade 2 or greater gastrointestinal toxicities between the 3 arms of the study will be observed and used to determine the best regimen
* To assess the Pharmacokinetic profile of perifosine when given to patients under fed and fasted conditions * To evaluate changes in other ECG parameters associated with perifosine treatment (ventricular rate, PR interval, QRS interval, QT interval)
Phase I: To determine the MTD of perifosine in combination with bortezomib in patients previously treated with bortezomib. Phase II: The primary endpoint of the study was 6-month progression-free survival.
The maximum tolerated dose (MTD) is defined in which fewer than 33% of patients experienced dose limiting toxicity (DLT) attributable to the study drug(s), when at least six patients were treated at that dose and are evaluable for toxicity. A DLT will be defined as any of the following deemed to be related to study drug(s): * Grade 3 non-hematologic toxicity except alopecia not reversible to Grade 2 or less within 96 hours * Any Grade 4 toxicity DLT will be based on the first cycle of treatment (first 21 days). Toxicity will be graded according to the NCI CTCAE version 3.0. To be evaluable for toxicity, a patient must receive at least 1 complete course of treatment or have experienced DLT.
Clinical Benefit Rate is defined as the radiographic response rate plus 6-month progression-free survival (PFS) rate.
| Arm | Type | Description |
|---|---|---|
| Perifosine + Capecitabine | ACTIVE_COMPARATOR | Perifosine 1 tablet daily + Capecitabine BID days 1 - 14 every 21 days |
| Placebo + Capecitabine | PLACEBO_COMPARATOR | Placebo 1 tablet daily + Capecitabine BID days 1 - 14 every 21 days |
| Group A: chondrosarcoma | EXPERIMENTAL | Patients with sarcoma subtype: histologically or cytologically confirmed diagnosis of chondrosarcoma. Supportive Care Guidelines for perifosine include antiemetic prophylaxis (antiemetics will be administered at the treating investigator's discretion), diarrhea management (loperamide), and hyperuricemia prophylaxis (allopurinol). |
| Group B: alveolar soft part sarcoma | EXPERIMENTAL | Patients with sarcoma subtype: histologically or cytologically confirmed diagnosis of alveolar soft part sarcoma. Supportive Care Guidelines for perifosine include antiemetic prophylaxis (antiemetics will be administered at the treating investigator's discretion), diarrhea management (loperamide), and hyperuricemia prophylaxis (allopurinol). |
| Group C: extra-skeletal myxoid | EXPERIMENTAL | Patients with sarcoma subtype: histologically or cytologically confirmed diagnosis of extra-skeletal myxoid chondrosarcoma. Supportive Care Guidelines for perifosine include antiemetic prophylaxis (antiemetics will be administered at the treating investigator's discretion), diarrhea management (loperamide), and hyperuricemia prophylaxis (allopurinol). |
| Perifosine 100 mg/d + imatinib mesylate | EXPERIMENTAL | Perifosine 100 mg/d x 28 days Oral daily dose of perifosine 100 mg and oral daily dose of imatinib mesylate (current dose at time of progression of disease \[PD\] without interruption). Both drugs will be taken on a continuous basis and should be taken with food. Each cycle will be defined as 28 days. |
| Perifosine 900 mg/d + imatinib mesylate | EXPERIMENTAL | Perifosine 900 mg/d (300 mg tid), 1 x weekly Oral once-weekly dose of perifosine 900 mg (300 mg tid) + oral daily dose of imatinib mesylate (current dose at time of PD without interruption). Perifosine will be taken on days 1, 8, 15, and 22 of a 28-day cycle. Both medications should be taken with food. |
| Perifosine | EXPERIMENTAL | Perifosine will be administered orally at 100mg PO daily with food. One treatment cycle will consist of 42 days (6 weeks). |
| Perifosine daily | EXPERIMENTAL | Patients will take three 50 mg tablets of perifosine daily at bedtime with food. Patients will be examined every three weeks. If patients have no progression it is allowed to receive 8 cycles of perifosine |
| Perifosine daily + Dexa twice per week | EXPERIMENTAL | Patients will take three 50 mg tablets of perifosine daily at bedtime with food until progression. If progressive disease is confirmed by a second measurement at least one week later the patient will receive a combination of 20 mg twice per week dexamethasone (dexa) and 150 mg perifosine daily at bedtime. |
| Group 1 on Perifosine | EXPERIMENTAL | Patients with AML, MDS, CML-BP non-lymphoid, CMML, or Agnogenic Myeloid Metaplasia (AMM). After a one-time loading dose of 600 mg (150 mg x 4 at least 4 hours apart) during the first cycle, perifosine will be given orally at 100 mg once a day continuously. Cycles are 28 days in length. Intra-patient dose escalation for the maintenance dose to 150 mg daily will be done in the second cycle if no non-hematological toxicities beyond grade 0-1 occurred during the first cycle are observed. |
| Group 2 on Perifosine | EXPERIMENTAL | Patients with CLL, ALL, or CML-BP lymphoid. After a one-time loading dose of 600 mg (150 mg x 4 at least 4 hours apart) during the first cycle, perifosine will be given orally at 100 mg once a day continuously. Cycles are 28 days in length. Intra-patient dose escalation for the maintenance dose to 150 mg daily will be done in the second cycle if no non-hematological toxicities beyond grade 0-1 occurred during the first cycle are observed. |
| Group A | EXPERIMENTAL | Patients in group A will have previously failed a VEGF receptor inhibitor but not an mTOR inhibitor.Intervention: Perifosine. |
| Group B | EXPERIMENTAL | Patients in group B will have failed both a VEGF receptor inhibitor and an mTOR inhibitor. Intervention: Perifosine. |
| Perifosine Daily Dose | EXPERIMENTAL | Daily dose perifosine 50 mg. |
| Perifosine Twice Daily Dose | EXPERIMENTAL | Twice daily dose perifosine 50 mg. |
| Arm 1: Perifosine + Capecitabine | EXPERIMENTAL | Perifosine 50 mg/d qd + Capecitabine 825 mg/m\^2 BID days 1 - 14 q 3 weeks until progression |
| Arm 2: Perifosine Placebo + Capecitabine | PLACEBO_COMPARATOR | Perifosine Placebo 50 mg/d qd + Capecitabine 825 mg/m\^2 BID days 1 - 14 q 3 weeks until progression |
| Perifosine 150 mg qd | ACTIVE_COMPARATOR | A daily dose of 150 mg to be given in one dose at bedtime. If patients experience no grade 2 toxicities during their first month of therapy, the dose will be escalated to 200 mg to be given in one dose at bedtime. |
| Perifosine 900 mg per week | ACTIVE_COMPARATOR | A weekly dose of 900 mg to be divided into three doses of 300 mg each. If patients experience no grade 2 toxicities during their first month of therapy, the dose will be escalated to 1,200 mg divided into four doses of 300 mg. |
| Perifosine 50 mg tid | ACTIVE_COMPARATOR | A daily dose of 150 mg to be divided into three doses of 50 mg each. If patients experience no grade 2 toxicities during their first month of therapy, the dose will be escalated to 200 mg divided into four doses of 50 mg. |
| Perifosine 100 mg | EXPERIMENTAL | Perifosine 100 mg orally daily under Fed and Fasted conditions |
| Phase II: Perifosine + Bortezomib | EXPERIMENTAL | All patients will start with perifosine at bedtime daily and Bortezomib IV on days 1, 4, 8, and 11 q 21 days. Patients will be evaluated at q 3 weeks. If the patient has a CR, PR, MR or stable disease, they will continue treatment. |
| Phase II: Perifosine + Bortezomib + Dexa | EXPERIMENTAL | If the patient shows progressive disease, dexamethasone 20 mg will be added on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 18, and 19 to perifosine at bedtime and bortezomib IV on days 1, 4, 8, and 11 q 21 days. |
| Phase I: Dose 1: Perifosine + Bortezomib | EXPERIMENTAL | Perifosine 50 mg at bedtime and bortezomib 1 mg/m2 on days 1, 4, 8, and 11 every 3 weeks. |
| Phase I: Dose 2: Perifosine + Bortezomib | EXPERIMENTAL | Perifosine 100 mg at bedtime and bortezomib 1 mg/m2 on days 1, 4, 8, and 11 every 3 weeks |
| Phase I: Dose 3: Perifosine + Bortezomib | EXPERIMENTAL | Perifosine 50 mg at bedtime and bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 every 3 weeks |
| Phase I: Dose 4: Perifosine + Bortezomib | EXPERIMENTAL | Perifosine 100 mg at bedtime and bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 every 3 weeks |
| Perifosine +Capecitabine | EXPERIMENTAL | One cycle of therapy will be defined as 3 weeks (21 days). Perifosine 50 mg qd (Days 1-21) + Capecitabine 1000 mg/m2 BID (Days 1-14). |
| Perifosine + Sorafenib | EXPERIMENTAL | - |
| Perifosine+Sunitinib malate | EXPERIMENTAL | - |
| Perifosine D1 + Docetaxel | EXPERIMENTAL | - |
| Perifosine D1+ Docexatel+Prednisone | EXPERIMENTAL | - |
| Perifosine+ D1,8 and 15+Docetaxel+Prednisone | EXPERIMENTAL | - |
| Surgical Cohort - cytoreductive surgery | OTHER | Cytoreductive surgery planned (surgical cohort). After post-operative standard evaluations, patients will resume therapy. After anti-emetic prophylaxis, patients will receive the first divided dose of the perifosine loading dose after recovery from surgery. Patients will be observed for at least 30 minutes to ensure there has been adequate anti-emetic prophylaxis, and then patients will receive temsirolimus administered over 30-60 minutes IV. The remaining divided doses of the perifosine loading dose will then be administered. Patients will then return weekly for infusion of temsirolimus over 30-60 minutes IV. Dosing will be continuous although for the purposes of evaluation, a cycle will be defined as 4 weeks (28 days). |
| Medical Cohort - no cytoreductive surgery | OTHER | No-Cytoreductive surgery planned (medical cohort). After anti-emetic prophylaxis, patients will receive the first divided dose of the perifosine loading dose. Patients will be observed for at least 30 minutes to ensure there has been adequate anti-emetic prophylaxis, and then patients will receive temsirolimus administered over 30-60 minutes IV. The remaining divided doses of the perifosine loading dose will then be administered. Patients will then return weekly for infusion of temsirolimus over 30-60 minutes IV. Dosing will be continuous although for the purposes of evaluation, a cycle will be defined as 4 weeks (28 days). |
| perifosine + temsirolimus | EXPERIMENTAL | This is a single arm, phase I study. Eligible patients will receive a loading dose of oral perifosine on the first day, followed by a maintenance dose starting on the second day until progression. Each patient is assigned to a group according to their body surface area (BSA). Temsirolimus will be combined with perifosine at four dose levels to determine the MTD for the combination therapy. Temsirolimus dosing will start on the same day as the perifosine load. |
| Name | Type | Description |
|---|---|---|
| Capecitabine | DRUG | 1000 mg/m2 BID/ Days 1-14 |
| Perifosine | DRUG | 50 mg daily x 21 days |
| Placebo | DRUG | 1 pill daily x 21 days |
| Loperamide | OTHER | All patients should be instructed to take loperamide at the earliest signs of diarrhea and/or abdominal cramping after beginning perifosine. |
| Allopurinol | OTHER | Patients with a known history of hyperuricemia and/or gout should receive prophylactic treatment with allopurinol 300 mg po daily. |
| Antiemetics | OTHER | Antiemetic prophylaxis will be administered at the treating investigator's discretion. |
| Imatinib Mesylate | DRUG | - |
| dexamethasone | DRUG | 20 mg twice weekly |
| Perifosine Placebo | OTHER | Placebo to Perifosine 50 mg/d qd |
| Bortezomib | DRUG | Phase I: Patients will receive 1 mg/m2 or 1.3 mg/m2 on days 1, 4, 8, and 11 every 3 weeks. Phase II: Patients will receive bortezomib on days 1,4,8 and 11 every 3 weeks. |
| Sorafenib | DRUG | For the purposes of this study, one cycle of therapy will be defined as 4 weeks. Patients will take perifosine one to three times a day and will also receive sorafenib one to two times a day. |
| Sunitinib Malate | DRUG | Sunitinib oral dose |
| Gemcitabine | DRUG | - |
| Paclitaxel | DRUG | Paclitaxel IV |
| Docetaxel | DRUG | IV administration |
| Prednisone | DRUG | Oral administration |
| Cytoreductive surgery | PROCEDURE | Standard of care/routine cytoreductive glioma resection surgery. Arm B only. |
| Temsirolimus | DRUG | Temsirolimus is an intravenous drug approved by the FDA for treatment of other cancers (kidney cancer, certain types of lymphoma) but not for brain tumors. |
| perifosine + temsirolimus | DRUG | The patient will take oral tablets of perifosine at a dose and frequency to be determined their height, weight and time when they enter the study as those entering early will be treated with lower dose levels (dosing frequency will vary from once a week to daily). The patient will receive an intravenous injection of temsirolimus once a week at a dose to be determined by their height, weight and time when they enter the study as those entering early will be treated with lower doses. In addition they will be asked to keep a medicine diary. |
| Lenalidomide | DRUG | Lenalidomide given in either 15 or 25 mg / day |
Inclusion Criteria: * Patients must have failed available therapy for the treatment of advanced colorectal cancer, including fluoropyrimidine, irinotecan, oxaliplatin, bevacizumab and for K-ras wild-type (WT) patients, anti-EGFR antibody (cetuximab or panitumumab) containing therapies. * For oxalip...
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Perifosine plus temsirolimus is an investigational combination of two small molecule anticancer agents studied in oncology. Perifosine is an oral alkylphospholipid, and temsirolimus is an mTOR inhibitor. The combination has been evaluated in Phase 1 clinical trials for recurrent brain tumors and pediatric solid tumors. It is not an approved therapy.
Perifosine plus temsirolimus has been studied in clinical trials for recurrent or progressive malignant gliomas, including glioblastoma, anaplastic astrocytoma, and anaplastic oligodendroglioma, as well as for recurrent pediatric solid tumors. It is an investigational combination and has not been approved for any indication.
COSCIENS Biopharma Inc., which trades under the ticker CSCI, is the developer associated with the perifosine plus temsirolimus clinical program. The company has sponsored Phase 1 trials of the combination in recurrent brain tumors and pediatric solid tumors.
Perifosine plus temsirolimus is in Phase 1 clinical development. The combination has been tested in Phase 1 trials, and all three trials listed for the combination are completed. It is investigational and has not been approved by the FDA for any indication.
The combination has been evaluated in completed Phase 1 trials, including NCT02238496, which studied perifosine and temsirolimus for recurrent or progressive malignant gliomas, and NCT01049841, which studied the combination in recurrent pediatric solid tumors. Both trials were conducted in the United States.
Perifosine plus temsirolimus is a combination regimen that includes perifosine, an oral alkylphospholipid, together with temsirolimus, an mTOR inhibitor. Perifosine alone has also been studied in other trials, such as NCT01224730 and NCT01097018, but the combination refers specifically to the two drugs used together.