Tag Archives: liver metastases

FDA Approves Clinical Protocol for Additional Phase 1 Study of TKM-PLK1 in Primary Liver Cancer or Liver Metastases

Posted on by

The U.S. Food and Drug Administration approves the clinical protocol for an additional Phase 1 study of TKM-PLK1 in patients with either primary liver cancer or liver metastases associated with select cancers including ovarian.

RNA Interference

Nucleic acids are molecules that carry genetic information and include DNA (deoxyribonucleic acid) and RNA (ribonucleic acid). Together these molecules form the building blocks of life. DNA contains the genetic code or “blueprint” used in the development and functioning of all living organisms, while one type of RNA (i.e., “messenger RNA” or mRNA) helps to translate that genetic code into proteins by acting as a messenger between the DNA instructions located in the cell nucleus and the protein synthesis which takes place in the cell cytoplasm (i.e., outside the cell nucleus, but inside the outer cell membrane). Accordingly, DNA is first copied or transcribed into mRNA, which, in turn, gets translated or synthesized into protein.

The molecular origin of many diseases results from either the absence or over-production of specific proteins. “RNA interference” (RNAi) is a mechanism through which gene expression is inhibited at the translation stage, thereby disrupting the protein production. RNAi is considered one of the most important discoveries in the field of molecular biology. Andrew Fire, Ph.D., and Craig C. Mello, Ph.D. shared the 2006 Nobel Prize in Physiology or Medicine for work that led to the discovery of the RNAi mechanism.  Because many diseases – cancer, metabolic, infectious and others – are caused by the inappropriate activity of specific genes, the ability to silence genes selectively through RNAi offers the potential to revolutionize the way we treat disease and illness by creating a new class of drugs aimed at eliminating specific gene-products or proteins from the cell. RNAi has been convincingly demonstrated in preclinical models of oncology, influenza, hepatitis, high cholesterol, diabetes, macular degeneration, Parkinson’s disease, and Huntington’s disease.

Small Interfering RNA 

While the mechanism itself is termed “RNAi,” the therapeutic agents that exert the effect are known as “small interfering RNAs” or siRNAs. Sequencing of the human genome has provided the information needed to design siRNA therapeutics directed against a wide range of disease-causing proteins. Based on the mRNA sequence for the target protein, a siRNA therapeutic can be designed relatively quickly compared to the time needed to synthesize and screen conventional small molecule drugs. Moreover, siRNA-based therapeutics are able to bind to a target protein mRNA with great specificity. When siRNA are introduced into the cell cytoplasm they are rapidly incorporated into an “RNA-induced silencing complex” (RISC) and guided to the target protein mRNA, which is then cut and destroyed, preventing the subsequent production of the target protein. The RISC can remain stable inside the cell for weeks, destroying many more copies of the target mRNA and maintaining target protein suppression for long periods of time.

To our knowledge, there are no siRNAs approved yet for medical use outside of a clinical trial, however, a number of R&D initiatives and clinical trials are currently underway, with one of the main areas of research focused on delivery. Because siRNAs are large, unstable molecules, they are unable to access target cells. Delivery technology is required to stabilize these drugs in the human blood stream, allow efficient delivery to the target cells, and facilitate uptake and release into the cell cytoplasm. Tekmira Pharmaceuticals Corporation, a leading developer of RNAi therapeutics has focused its research on identifying lipid nanoparticles (LNPs) that can overcome the challenges of delivering siRNAs.

TKM-PLK1 

TKM-PLK1 is being developed as a novel anti-tumor drug in the treatment of cancer. LNPs are particularly well suited for the delivery of siRNA to treat cancer because the lipid nanoparticles preferentially accumulate within tissues and organs having leaky blood vessels, such as cancerous tumors. Once at the target site, LNPs are taken up by tumor cells and the siRNA payload is delivered inside the cell where it reduces expression of the target protein. Through careful selection of the appropriate molecular targets, LNPs are designed to have potent anti-tumor activity yet be well tolerated by healthy tissue adjacent to the tumor.

Tekmira has taken advantage of this passive targeting effect to develop an siRNA directed against PLK1 (polo-like kinase 1), a protein involved in tumor cell proliferation. Inhibition of PLK1 prevents the tumor cell from completing cell division, resulting in cell cycle arrest and cell death.

Because the standard of care for cancer treatment often involves the use of drug combination therapies, Tekmira has selected gene targets for its oncology applications that synergize with conventional drugs that are currently in use. TKM-PLK1 has the potential to provide both direct tumor cell killing and sensitization of tumor cells to the effects of chemotherapy drugs.

Phase 1 Study of TKM-PLK1 in Primary Liver Cancer or Liver Metastases

Tekmira, along with its collaborators at the U.S. National Cancer Institute (NCI), announced that they have received approval from the U.S. Food and Drug Administration (FDA) to proceed with a new Phase 1 clinical trial for Tekmira’s lead oncology product, TKM-PLK1. This trial, run in parallel with the ongoing Phase 1 trial of TKM-PLK1 (for adult patients with solid tumors or lymphomas that are refractory to standard therapy), provides Tekmira with an early opportunity to validate the mechanism of drug action.

“Patients in this new study, who will have either primary liver cancer or liver metastases, will receive TKM-PLK1 delivered directly into the liver via Hepatic Artery Infusion (HAI). The trial design will allow us to measure tumor delivery, polo-like kinase 1 (PLK1) messenger RNA knockdown, and RNA interference (RNAi) activity in tumor biopsies from all of the patients treated,” said Dr. Mark J. Murray, Tekmira’s President and CEO.

“This NCI clinical trial will run in parallel with our multi-center TKM-PLK1 solid tumor Phase 1 trial, currently underway at three centers in the United States. Working together on this clinical trial with our collaborators at the NCI will allow us to develop an even more robust data package to inform subsequent TKM-PLK1 development. We expect to have interim TKM-PLK1 clinical data before the end of 2011,” added Dr. Murray.

The NCI trial is a Phase 1 multiple-dose, dose escalation study testing TKM-PLK1 in patients with unresectable colorectal, pancreatic, gastric, breast, ovarian and esophageal cancers with liver metastases, or primary liver cancers. These patients represent a significant unmet medical need as they are not well served by currently approved treatments.

The primary objectives of the trial include evaluation of the feasibility of administering TKM-PLK1 via HAI, and characterization of the pharmacokinetics and pharmacodynamics of TKM-PLK1. Pharmacodynamic measurements will examine the effect of the drug on the patient’s tumors, specifically aiming to confirm PLK1 knockdown and RNAi activity. Typically reserved for later stage trials, pharmacodynamic measurements are facilitated in this Phase 1 trial in part through the unique capabilities of the NCI Surgery Branch. Secondary objectives of the trial include establishing maximum tolerated dose and to evaluate response rate.

About the National Cancer Institute

The National Cancer Institute (NCI) is one of 27 institutes and centers under the oversight of the U.S. National Institutes of Health (NIH), and is the primary cancer medical research agency in the U.S. The TKM-PLK1 trial will involve investigators at the NCI’s Center for Cancer Research (CCR) on the main NIH campus located in Bethesda, Maryland. The CCR is home to more than 250 scientists and clinicians working in intramural research at the NCI. CCR’s investigators include some of the worlds most experienced basic, clinical, and translational scientists who work together to advance our knowledge of cancer and develop new therapies.

About TKM-PLK1

TKM-PLK1 targets polo-like kinase 1, or PLK1, a cell cycle protein involved in tumor cell proliferation and a validated oncology target. Cancer patients whose tumors express high levels of PLK1 have a relatively poor prognosis. Inhibition of PLK1 prevents tumor cells from completing cell division, resulting in cell cycle arrest and cancer cell death.

About RNAi and Tekmira’s LNP Technology

RNAi therapeutics have the potential to treat a broad number of human diseases by “silencing” disease causing genes. The discoverers of RNAi, a gene silencing mechanism used by all cells, were awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi therapeutics, such as “siRNAs,” require delivery technology to be effective systemically. LNP technology is one of the most widely used siRNA delivery approaches for systemic administration. Tekmira’s LNP technology (formerly referred to as “stable nucleic acid-lipid particles” or SNALP) encapsulates siRNAs with high efficiency in uniform lipid nanoparticles which are effective in delivering RNAi therapeutics to disease sites in numerous preclinical models. Tekmira’s LNP formulations are manufactured by a proprietary method which is robust, scalable and highly reproducible and LNP-based products have been reviewed by multiple FDA divisions for use in clinical trials. LNP formulations comprise several lipid components that can be adjusted to suit the specific application.

About Tekmira Pharmaceuticals Corporation

Tekmira Pharmaceuticals Corporation is a biopharmaceutical company focused on advancing novel RNAi therapeutics and providing its leading lipid nanoparticle delivery technology to pharmaceutical partners. Tekmira has been working in the field of nucleic acid delivery for over a decade and has broad intellectual property covering LNPs. Further information about Tekmira can be found at www.tekmirapharm.com. Tekmira is based in Vancouver, British Columbia, Canada.

Source

Clinical Trial Information

  • A Phase 1 Dose Escalation Study to Determine the Safety, Pharmacokinetics, and Pharmacodynamics of Intravenous TKM-080301 [a/k/a TKM-PLK1 or PLK1 SNALP] in Patients With Advanced Solid Tumors [or Lymphomas], ClinicalTrials.gov Identifier: NCT01262235. [Note: This clinical trial summary relates to the ongoing Phase 1 TKM-PLK1  solid tumor clinical trial. We will post the second Phase 1 TKM-PLK1 clinical trial summary with respect to primary liver cancer and liver metastases once it becomes publicly available]
Additional Information
  • Wang J, et al. Delivery of siRNA therapeutics: barriers and carriers. AAPS J. 2010 Dec;12(4):492-503. Epub 2010 Jun 11. Review. PubMed PMID: 20544328; PubMed Central PMCID: PMC2977003.

High-Dose Stereotactic Body Radiation Therapy Effective Treatment For Patients With Low Volume Lung or Liver Metastases

Posted on by

Libby’s H*O*P*E*™ previously reported on potential treatments for “oligometastasis,” which is defined as cancer that spreads to a few distant body sites, on June 23, 2008 and August 17, 2008.  Two related U.S. multi-institutional, phase I/II clinical studies and one Canadian Phase I clinical study reported recently results from an evaluation of the efficacy and tolerability of high-dose stereotactic body radiation therapy (SBRT) for the treatment of patients with liver or lung metastases.  A description of each study and its findings is provided below.  In addition, we have provided an excerpt from an editorial published in the Journal of Clinical Oncologythat comments upon the lessons learned from the three SBRT clinical studies described below, as well as other related studies.

Libby’s H*O*P*E*™ previously reported on potential treatments for “oligometastasis,” which is defined as cancer that spreads to a few distant body sites, on June 23, 2008 and August 17, 2008.  Two related U.S. multi-institutional, phase I/II clinical studies and one Canadian Phase I clinical study reported recently results from an evaluation of the efficacy and tolerability of high-dose stereotactic body radiation therapy (SBRT) for the treatment of patients with liver or lung metastases.  A description of each study and its findings are provided below.  In addition, we have provided an excerpt from an editorial published in the Journal of Clinical Oncology that comments upon the lessons learned from the three SBRT clinical studies described below, as well as other related studies.

sbrtU.S. SBRT Liver Metastases Study

In the first U.S. clinical study, patients with one to three hepatic lesions (with maximum individual tumor diameters less than 6 cm) were enrolled and treated on a multi-institutional, phase I/II clinical trial in which they received SBRT delivered in three fractions. During the phase I clinical study, the total radiation dose was safely escalated from 36 Gy to 60 Gy. During the phase II portion of the clinical study, the dose was 60 Gy. The study primary end point was local control of the hepatic metastases. Hepatic metastatic lesions with at least 6 months of radiographic follow-up were considered assessable for local control. The study secondary end points were toxicity and survival.

As part of this clinical study, 47 patients with 63 lesions were treated with SBRT. Among those patients, 69% had received at least one prior systemic therapy regimen for metastatic disease (range, 0 to 5 regimens), and 45% had extra-hepatic disease at study entry. Forty-nine discrete lesions were assessable for local control. Median follow-up for assessable lesions was 16 months (range, 6 to 54 months). The median maximal tumor diameter was 2.7 cm (range, 0.4 to 5.8 cm). Based upon this criteria, the researchers reported the following findings:

  • Only one patient experienced grade 3 or higher toxicity (2%);
  • Local progression occurred in only three lesions at a median of 7.5 months (range, 7 to 13 months) after SBRT;
  • Actuarial in-field local control rates at one and two years after SBRT were 95% and 92%, respectively;
  • Among lesions with maximal diameter of 3 cm or less, 2-year local control was 100%; and
  • Median survival was 20.5 months.

Based upon the foregoing, the U.S. researchers concluded that the multi-institutional, phase I/II clinical study demonstrates that high-dose liver SBRT is safe and effective for the treatment of patients with one to three liver metastases.

Canadian SBRT Liver Metastases Study

In the phase I Canadian clinical study, patients with liver metastases who were inoperable or medically unsuitable for resection, and were not candidates for standard therapies, were eligible for this individualized SBRT study. Individualized radiation doses were chosen to maintain the same nominal risk of radiation-induced liver disease (RILD) for three estimated risk levels (5%, 10%, and 20%).  Additional patients were treated at the maximal study dose (MSD) in an expanded cohort.  Median SBRT dose was 41.8 Gy (range, 27.7 to 60 Gy) in six fractions over 2 weeks.  Based upon this criteria, the Canadian researchers reported the following findings:

  • Sixty-eight patients with inoperable colorectal (n = 40), breast (n = 12), or other (n = 16) liver metastases were treated;
  • Median tumor volume was 75.2 mL (range, 1.19 to 3,090 mL);
  • The highest RILD risk level investigated was safe, with no dose-limiting toxicity;
  • Two patients experienced grade 3 liver enzyme changes, but no RILD or other grade 3 to 5 liver toxicity was seen, resulting in a low estimated risk of serious liver toxicity;
  • Six patients (9%) experienced acute grade 3 toxicities (two gastritis, two nausea, lethargy, and thrombocytopenia) and one (1%) patient experienced grade 4 toxicity (thrombocytopenia);
  • The 1-year local control rate was 71%; and
  • The median overall survival was 17.6 months.

Based upon the foregoing, the Canadian researchers concluded that individualized six-fraction liver metastases SBRT is safe, with sustained local control observed in the majority of patients.

U.S. SBRT Lung Metastases Study

In the third study, patients with one to three lung metastases (with cumulative maximum tumor diameter smaller than 7 cm) were enrolled and treated as part of a U.S. multi-institutional phase I/II clinical study in which they received SBRT delivered in 3 fractions.  During the phase I clinical study, the total dose was safely escalated from 48 to 60 Gy. During the phase II portion of the clinical study, the phase II dose was 60 Gy.  The study primary end point was local control.  Metastatic lung lesions with at least 6 months of radiographic follow-up were considered assessable for local control.  The study secondary end points included toxicity and survival.

As part of this study, 38 patients with 63 lesions were enrolled and treated at three U.S. participating institutions. Among those patients, 71% received at least one prior systemic regimen for metastatic disease and 34% had received at least two prior regimens (range, 0 to 5 regimens). Two patients had local recurrence after prior surgical resection. Fifty lesions were assessable for local control.  Median follow-up for assessable lesions was 15.4 months (range, 6 to 48 months). The median gross tumor volume was 4.2 mL (range, 0.2 to 52.3 mL). Based upon this criteria, the researchers reported the following findings:

  • There was no grade 4 toxicity;
  • The incidence of any grade 3 toxicity was 8% (3 of 38 patients);
  • Symptomatic pneumonitis occurred in one patient (2.6%);
  • Actuarial local control at one and two years after SBRT was 100% and 96%, respectively;
  • Local progression occurred in one patient, 13 months after SBRT; and
  • Median survival was 19 months.

Based upon the foregoing, the U.S. researchers concluded that the multi-institutional phase I/II clinical study demonstrates that high-dose SBRT is safe and effective for the treatment of patients with one to three lung metastases.

Using a Bigger Hammer: The Role of Stereotactic Body Radiotherapy in the Management of Oligometastases – Journal of Clinical Oncology Editorial

“… What can we learn from these three trials [described above]?

First, we have learned once again that it is possible to conduct prospective trials of new technological approaches. This is an important lesson. This is how future technologies, such as proton therapy, should be tested.

Second, although the poor overall survival of patients in these trials competes with the risk of local relapse, possibly leading to overestimation of the probability of local control at 2 years, it seems likely that SBRT is a good treatment for such patients. It would seem that a standardized dose/fractionation scheme, such as 60Gyin three fractions, works well for tumors smaller than 3 cm; larger ones may benefit from an individualized approach, such as described by Lee et al. [Canadian study decribed above, ftnote omitted]. However, we must continue to remember past experiences with hypofractionation of large volumes, which can produce severe late normal-tissue effects, especially fibrosis. Even if small volumes are irradiated, catastrophic complications can occur.  In the case of lung cancer, severe unacceptable complications (bronchial fibrosis or hemorrhage) have been associated with treatment of lesions within 2 cm of major airways.  A more protracted (five-fraction) regimen is about to be tested in a Radiation Therapy Oncology Group (RTOG) trial that will open in the coming months that will determine if these toxicities can be avoided.  Lesions close to the chest wall may also benefit from a more protracted fractionation to avoid rib fractures.  In the case of medial or central liver lesions, hypofractionation can cause intestinal obstruction or biliary fibrosis.

Finally, we should recognize that the methodology used in these trials applies to patients with relatively normal liver and lung functions.  At this time, it is not clear how to account for organ dysfunction in patients with lung cancer or primary liver tumors.  Certainly, differences in tolerance to radiation between patients with liver metastases and those with primary liver tumors have been observed before [ftnote omitted].  Therefore, although SBRT seems to have given us a bigger hammer, we still have much to learn about how and when to strike the nails.”

Primary Sources: