CancerPhase 1NCT01705002

Intravenously Administered Pegylated Liposomal Mitomycin-C Lipid-based Prodrug (PROMITIL) in Cancer Patients With Solid Tumors.

A Phase 1 study testing Promitil, Capecitabine and Bevacizumab in people with Cancer and Solid Tumor, run by Lipomedix Pharmaceuticals Inc. at 4 sites in Israel.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

This is a Phase I, multi-center, Dose-Escalating, Safety Study of an Intravenously Administered Pegylated Liposomal Mitomycin-C Lipid-based Prodrug (PL-MLP, PROMITIL) in Cancer Patients with Solid Tumors. Read more about this study

Who is it for?: Ages 18 to 80 years
Conditions the study is for: Cancer, Solid Tumor, Metastatic Colorectal Cancer (mCRC)
What is being tested?: Promitil, Capecitabine and Bevacizumab
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 88 participants
Where: 4 sitesIsrael
Study dates: Oct 2012to Jun 2018
Phase: Phase 1

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 80 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Patients diagnosed with inoperable, recurrent or metastatic malignant solid tumors, deemed incurable, and who have either:
Failed to respond to standard therapy or
For whom no standard therapy is available or
Refuse to receive standard therapies
Histologically or cytologically confirmed diagnosis of solid tumor on file.
Age 18-80 years

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BMI: 18-36
ECOG Performance Status ≤ 2
Estimated life expectancy of at least 3 months
Adequate bone marrow function (an absolute neutrophil count ≥1500/mm3, hemoglobin ≥9.5 g/dl, HgbA1C≤7%, and a platelet count ≥100,000/mm3(
Adequate liver function (serum bilirubin ≤2.0 mg/100 ml; alanine aminotransferase ≤2× ULN)
Adequate renal function (serum creatinine ≤1.5 mg/100 ml or creatinine clearance ≥45 ml/min/1.73m2)
No prior intravenous treatment with Mitomycin-C either alone or in combination
No other myelosuppressive treatment within 4 weeks before start of the study drug.
No other anti-cancer treatment within 2 weeks before start of the study drug
No prior extensive radiotherapy (e.g., whole pelvis total neuroaxis or greater than 50% of neuroaxis, whole abdomen, whole body or half-body) or bone marrow transplantation with high dose chemotherapy and/or total body irradiation. Re-irradiation of a field in abdomen/pelvis will be considered as extensive radiotherapy, excluding such patients from the study.
Women of child bearing potential practicing an acceptable method of birth control.
Understanding of study procedures and willingness to comply for the entire length of the study and to give written informed consent.
Additional criteria only for the Expanded Cohort and both Combination cohorts: Patients with histologically or cytologically confirmed recurrent and/or metastatic measurable or nonmeasurable CRC, with tissue or cytological diagnosis of cancer on file.
Additional criteria only for the Expanded Cohort and both Combination cohort: Patients who demonstrated either progression or intolerance when treated with irinotecan and fluopyrimidine-based chemotherapy, and, in the case of K-ras wild type tumors, anti-EGFR antibodies (Cetuximab, Panitumumab). Prior treatment with oxaliplatin or bevacizumab is allowed but not required.
Additional criteria only for the Expanded Cohort and both Combination cohorts: A ≥28 day treatment-free interval between last chemotherapeutic treatment and first treatment with Promitil, with the exception of Capecitabine and biological therapies, where 14-day treatment-free intervals suffice. this is also relevant for patients in the Combination Cohort that are currently taking Capecitabine prior to enter the study).
Additional criteria for the Triple Combination Cohort with bevacizumab only: Prior exposure to oxaliplatin should have terminated at least 6 months before start of PROMITIL, whether given as adjuvant therapy or as therapy for metastatic disease.
Additional criteria for the triple Combination Cohort with bevacizumab only: A ≥ 28 day treatment-free interval from last bevacizumab treatment

Who cannot join

Known hypersensitivity to the study drug or to any of its components
CHF (NYHA = Class IV) or LVEF≤40%
COPD > Stage 3 (FEV1<50%, FEV1/FVC<70%);
Cirrhosis (Child-Pugh Class C score);
Serum Albumin level < 3 g/dl
Any other severe concurrent disease which in the judgment of the investigator would make the subject inappropriate for entry into this study

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History of human immunodeficiency virus (HIV) infection
History of chronic active hepatitis including subjects who are carriers of hepatitis B virus (HBV) or hepatitis C virus (HCV).
Presence of uncontrolled infection.
Evidence of active bleeding or bleeding diathesis
Brain metastases in symptomatic patients requiring ≥4 mg dexamethasone/day. However, patients with treated brain metastases by surgery or radiation who are stable and symptom-free (<4 mg dexamethasone/day) for a minimum period of 4 weeks post-treatment are eligible.
Pregnant or lactating
Treatment with other investigational drugs within 14 days of start of the study drug for non-myelosuppressive agents, and within 28 days of start of the study drug for myelosuppressive agents.
Additional criteria for the Combination cohorts: Uncontrolled ascites (defined as 2 or more palliative taps in the last 30 days before screening).
Additional criteria for the Combination cohorts with bevacizumab only: uncontrolled clinically significant cardiac disease, hypertension, arrhythmias, or angina pectoris; acute myocardial infarction or cerebrovascular accident within 12 months of initiation of PROMITIL treatment.
Additional criteria for the Combination cohorts with bevacizumab only: Any contraindication for treatment with Bevacizumab (e.g active bleeding, recent extensive surgery).

Trial locations and contacts

4 sites in 1 country.

Israel4 sites

Rambam Health Care Campus
Haifa
Shaare Zedek Medical Center
Jerusalem
Chaim Sheba Medical center
Ramat Gan
Tel-Aviv Sourasky Medical Center
Tel Aviv, 64239

Other trials in Israel

About this study

Official title: A Phase I, Dose-Escalating, Safety Study of an Intravenously Administered Pegylated Liposomal Mitomycin-C Lipid-based Prodrug (PL-MLP, PROMITIL) in Cancer Patients With Solid Tumors.

Escalated cohorts A-H: 27 male or female participants, ages 18-80, BMI 18-36 diagnosed with inoperable, recurrent or metastatic malignant solid tumors, deemed incurable, and who have failed to respond to standard therapy or for whom no standard therapy is available. Eligible subjects will be assigned, successively in order of accrual, to one of eight cohorts, to receive escalating doses of intravenously infused PROMITIL. PROMITIL will be administered as an intravenous infusion. Dose escalation will only proceed in the absence of dose-limiting toxicity (DLT). For this purpose, each cohort will only begin its first cycle of PROMITIL when the cohort preceding it has successfully completed its first 4-week cycle without any signs of DLT.

Expanded cohort: 17 adult patients with metastatic CRC. The purpose of this expanded cohort is to further evaluate the safety of Promitil and to search for signs of antitumor activity of Promitil in this specific patient population.

Combination Cohort (Promitil concomitantly with Capecitabine): 23 adult patients with metastatic CRC.

Triple combination Cohort: 13 additional subjects with metastatic CRC, received combination of Promitil concomitantly with Bevacizumab (5 mg/kg) on day 1 of a 28 day cycle and Capecitabine on days 1-14 of a 28 day cycle.

3 weekly cohort- 9 subjects with metastatic CRC will receive Promitil and Bevacizumab (7.5 mg/kg) on day 1 of a 21 day cycle.

Read the detailed description

For all cohorts, PROMITIL will be administered as an intravenous infusion at an initial rate of 0.25mg/min followed by gradual increase to a maximal rate of 2mg/min until completion of dosing, if absence of infusion reactions is established and in line with most updated version of IFU available for this study.

For each subject, subsequent dosing will take place 28 days after the previous treatment, provided they are deemed fit to be dosed again.

Patients will return to the study center on days 8, 15, 22 of cycle 1, and on day 15 of cycles 2 and 3, for monitoring assessments.

All patients will be followed-up for survival and post-Promitil treatment. Patients who did not received 3 cycles of PROMITIL will be followed up only until PD.

For the 3 weekly cohort Promitil will be administered at 3 week interval together with Bevacizumab (7.5 mg/kg). Patients will return to the study center on days 8 and 15 of cycle 1, and on day 15 of cycles 2 and 3, for monitoring assessments.

Conditions: Cancer, Solid Tumor, Metastatic Colorectal Cancer (mCRC)
Being tested: Promitil, Capecitabine, Bevacizumab
Keywords: phase 1, dose escalating, prodrug, mitomycin C, Capecitabine
Medical subject headings: Neoplasms, Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

PromitilDrug
2 mg/kg dose IV
CapecitabineDrug
Also called Xeloda
1000 mg dose BID PO for days 1-21 for Combination Cohort and on day 1-14 on Triple combination Cohort
BevacizumabDrug
Also called Avastin
for Triple combination cohort an IV dose of 5 mg/kg on day 1 at 4 week interval. For the 3 weekly cohort an IV dose of 7.5 mg/kg at 3 week interval.

Study groups in NCT01705002
Study group	Role	What they receive
Cohort A: Promitil 0.5 mg/kg	Experimental	Three treatment cycles, intravenous infusion of Promitil Receives: Drug: Promitil
Cohort B: Promitil 1.0 mg/kg	Experimental	Three treatment cycles, intravenous infusion of Promitil Receives: Drug: Promitil
Cohort C: Promitil 1.5 mg/kg	Experimental	Three treatment cycles, intravenous infusion of Promitil Receives: Drug: Promitil
Cohort D: Promitil 2.0 mg/kg	Experimental	Three treatment cycles, intravenous infusion of Promitil Receives: Drug: Promitil
Cohort E: Promitil 2.5 mg/kg	Experimental	Three treatment cycles, intravenous infusion of Promitil Receives: Drug: Promitil
Cohort F: Promitil 3.0 mg/kg	Experimental	Three treatment cycles, intravenous infusion of Promitil Receives: Drug: Promitil
Cohort G: Promitil 3.5 mg/kg	Experimental	Three treatment cycles, intravenous infusion of Promitil Receives: Drug: Promitil
Cohort H: Promitil 4.0 mg/kg	Experimental	Three treatment cycles, intravenous infusion of Promitil Receives: Drug: Promitil
Expanded Cohort	Experimental	Patients treated with the selected RP2D of PROMITIL (3 mg/kg) intravenously administered on their first cycle and reduced dose of 2 mg/kg from cycle 2 and onwards. Only for mCRC patients. Receives: Drug: Promitil
Combination Cohort	Experimental	Patients treated with one cycle of 2.5mg/kg Promitil day 1 together with Capecitabine 1,000 mg bid po days 1-21 followed by two cycles of 2.0 mg/kg Promitil day 1 together with Capecitabine 1,000 mg bid po days 1-21, at four-week intervals. Only for mCRC patients. Receives: Drug: Promitil; Drug: Capecitabine
Triple combination Cohort	Experimental	Patients treated with one cycle of 2mg/kg Promitil I.v and 5 mg/kg Bevacizumab i.v on day 1 together with Capecitabine 1,000 mg bid p.o days 1-14 at four-week intervals. Only for mCRC patients. Receives: Drug: Promitil; Drug: Capecitabine; Drug: Bevacizumab
3 Weekly Cohort	Experimental	Patients treated with one cycle of 2mg/kg Promitil I.v and 7.5 mg/kg Bevacizumab i.v on day 1 together at three-week intervals. Only for mCRC patients. Receives: Drug: Promitil; Drug: Bevacizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

Maximal Tolerated Dose (MTD) of PROMITIL
Only DLTs occurring during the first cycle of treatment for each participant will determine MTD endpoint
Measured: First cycle of treatment (4 weeks)
Dose Limiting Toxicity (DLT) of PROMITIL
Measured: First cycle of treatment (4 weeks)
Pharmacokinetic (PK) profile of PROMITIL
PK assessments will monitor plasma levels of MLP and metabolite (MMC), as well as PK parameters (Cmax, AUC0-t, AUC 0-∞, MRT, t½ , Kel, Cl, VD).
Measured: 3 cycles of treatment (12 weeks)

Secondary outcomes (2)

Anti-tumor responses to the delivered PROMITIL regimens
Measured: 12 months
Toxicity profile of PROMITIL
Measured: 3 cycles of treatment (12 weeks)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Oct 2012Jun 2018

First posted12 Oct 2012 (estimated)
Study startOct 2012
Primary completionNov 2017
Study completionJun 2018

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (1)Papers the sponsor has linked to this study.
Other trials for CancerStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 88 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01705002
Sponsor's protocol ID: PROMITIL-01
Status last verified: Jul 2018
First submitted: 8 Oct 2012
Last updated: 10 Jul 2018
Results posted: No
Data monitoring committee: Yes

Publications

Golan T, Grenader T, Ohana P, Amitay Y, Shmeeda H, La-Beck NM, Tahover E, Berger R, Gabizon AA. Pegylated liposomal mitomycin C prodrug enhances tolerance of mitomycin C: a phase 1 study in advanced solid tumor patients. Cancer Med. 2015 Oct;4(10):1472-83. doi: 10.1002/cam4.491. Epub 2015 Jul 14.
PubMed 26172205